Imidazolyl derivatives as corticotropin releasing factor inhibitors

ABSTRACT

The present invention relates to novel heterocyclic antagonists of Formula (I) and pharmaceutical compositions comprising said antagonists of the corticotropin releasing factor receptor (“CRF receptor”)  
                 
 
     useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This divisional application claims priority from non-provisionalapplication Ser. No. 10/044,183 filed Jan. 11, 2002 which claimspriority from provisional application U.S. Ser. No. 60/264,570 filedJan. 26, 2001. The disclosures of these prior applications areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to antagonists and pharmaceuticalcompositions comprising said antagonists of the corticotropin releasingfactor receptor (“CRF receptor”) useful for the treatment of depression,anxiety, affective disorders, feeding disorders, post-traumatic stressdisorder, headache, drug addiction, inflammatory disorders, drug oralcohol withdrawal symptoms and other conditions the treatment of whichcan be effected by the antagonism of the CRF-1 receptor.

BACKGROUND OF THE INVENTION

[0003] It has been shown that the neuropeptide, corticotropin releasingfactor (“CRF”), acting through its binding to the CRF-1 receptor, is aprimary mediator of stress- and anxiety-related physiological responsesin humans and other mammals by stimulating ACTH secretion from theanterior pituitary gland. See A. J. Dunn, et al., Brain Res. Rev., 15:71-100 (1990). Antagonists of the CRF-1 receptor, both peptides (J.Gulyas, et al., Proc. Natl. Acad. Sci. U.S.A., 92: 10575-10579 (1995)and small molecules (J. R. McCarthy, et al., Curr. Pharm. Design, 5:289-315 (1999), have demonstrated the ability to ameliorate the effectsof stressful stimuli in several animal models. In addition, markedelevations of CRF in cerebrospinal fluid have been detected in a largeportion of individuals diagnosed with major depression and anxietydisorders, and the levels correlate with severity of the disease. See F.Holsboer, J. Psychiatric Res., 33: 181-214 (1999). Followingantidepressant treatment, the increased CRF levels observed in depressedpatients were reduced. See C. M. Banki, et al., Eur.Neuropsychopharmacol., 2: 107-113 (1992); see also Effects of thehigh-affinity corticotropin-releasing hormone receptor 1 antagonistR121919 in major depression: the first 20 patients treated. Zobel A W,Nickel T, Kunzel H E, Ackl N, Sonntag A. Ising M, Holsboer F J PsychiatrRes 2000, 34, 171-181. CRF has also been shown to be a key mediator ofseveral immune system functions through its effect on glucocorticoidplasma levels. See E. L. Webster, et al., Ann. N.Y. Acad. Sci., 840:21-32 (1998). Recent reviews of the activity of CRF-1 antagonistsinclude P. J. Gilligan, et al., J. Med. Chem., 43: 1641-1660 (2000) andJ. R. McCarthy, et al., Ann. Rep. Med. Chem., 34: 11-20 (1999). Thereappears a need to discover novel small molecule CRF antagonists in orderto treat a wide variety of human disorders including depression,anxiety, bipolar disorder, and other stress-related illnesses. See WO98/35967, WO 99/01454, WO 99/10350, wo 99/67247, 00/01675, WO 00/01697,WO 00/39127, WO 00/59907, WO 00/59908, EP 778277, EP 812831.

SUMMARY OF THE INVENTION

[0004] Thus according to a first embodiment of the first aspect of thepresent invention are provided compounds of Formula (I)

[0005] and pharmaceutically acceptable salts and solvates thereof

[0006] wherein

[0007] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0008] R² is C(D)NR³R⁴, D′-D″(R³)(R⁴) or CH₂NR³R⁴

[0009] D′ is CH₂ or a bond;

[0010] D″ is C, C—OH or CH

[0011]  wherein

[0012] said C is attached to R³ by a single or double bond;

[0013] said C is attached to R⁴ by a single or double bond;

[0014]  provided that

[0015] C is not attached to both R³ and R⁴ by double bonds;

[0016] said CH is attached to R³ and R⁴ by single bonds;

[0017] said C of C—OH is attached to R³ and R⁴ by single bonds;

[0018] Dis O or S;

[0019] R³ and R⁴ are each independently selected from the groupconsisting of H, C₁₋₆alkyl, C₁₋₆haloalkyl, —C₁₋₆hydroxyalkyl,—C₁₋₄alkylene-O—C₁₋₄alkyl, —C₁₋₃alkylene-C₁₋₆thioalkyl,—C₂₋₆alkylidene-(C₁₋₄alkoxy)₂, C₃₋₇cycloalkyl,—C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,—C₁₋₆alkylene-CN, —C₁₋₆alkylene-heterocyclo and —C₁₋₆alkylene-aryl;

[0020] wherein said aryl of said —C₁₋₆alkylene-aryl is optionallysubstituted with one to three of the same or different substituentsselected from the group consisting of fluoro, chloro, bromo, cyano,nitro, C₁₋₄alkyl and C₁₋₃alkoxy; or

[0021] R³ and R⁴ together with the nitrogen to which they are attachedform a five or six-membered heterocycle,

[0022] said heterocycle optionally containing one additional heteroatomselected from the group consisting of N, S and O; and

[0023] said heterocycle optionally substituted with one or more groupsselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, aryl,—C₁₋₄alkylene-aryl, pyridyl and halogen;

[0024]  wherein said aryl of said —C₁₋₄alkylene-aryl is optionallysubstituted with one to three of the same or different substituentsselected from the group consisting of fluoro, chloro, bromo, cyano,nitro and C₁₋₃alkoxy;

[0025] X is C;

[0026] Y is C;

[0027] A is

[0028]  wherein

[0029] X¹ is N and is attached to X;

[0030] Y¹ is N and is attached to Y;

[0031] G is

[0032]  wherein

[0033] Y² is N, CH, CH₂, C(O), C(S), CR⁵, CHR⁵ or CE¹ and is attached toY¹;

[0034] J is CH, CH₂, C(O), C(S), CR⁶, CHR⁶, a bond or CE²;

[0035] Z¹ is CH, CH₂, C(O), C(S), CR⁷, CHR⁷ or CE³ and is attached to Z;

[0036]  wherein

[0037] R⁵, R⁶ and R⁷ are each independently selected from the groupconsisting of —CN, —C₁₋₄alk(en)ylene-CN, halo, C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆alkynyl, C₁₋₆haloalkyl, aryl, —C₁₋₄alk(en)ylene-aryl,—C₁₋₄alk(en)ylene-heterocyclo, heterocyclo, —C₁₋₄alk(en)ylene-amino,—C₁₋₄alkylene-amino-C₁₋₄alkyl, aryl-amino, -amino-(C₁₋₆alk(en)yl)₁₋₂,-amino-aryl, -amino-heterocyclo, C₁₋₆alkoxy, —O-aryl and —O-heterocyclo;

[0038] E¹ and E² together form moieties selected from the groupconsisting of C₄-alk(en)lyene, N(CH)₃, CHN(CH)₂, N(CH)₂N, N═NCH═N andNCHNCH;

[0039]  wherein said moieties are optionally substituted with halogen,—CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, substituted or unsubstituted phenyl,hydroxy, C₁-C₄alkoxy, SH, C₁-C₄thioalkyl, NH₂, NH(C₁-C₄alkyl) orN(C₁-C₄alkyl)₂;

[0040] E² and E³ together form moieties selected from the groupconsisting of C₄-alk(en)lyene, N(CH)₃, CHN(CH)₂, N(CH)₂N, N═NCH═N andNCHNCH;

[0041]  wherein said moieties are optionally substituted with halogen,—CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, substituted or unsubstituted phenyl,hydroxy, C₁-C₄alkoxy, SH, C₁-C₄thioalkyl, NH₂, NH(C₁-C₄alkyl) orN(C₁-C₄alkyl)₂;

[0042] E¹ and E³ together form moieties selected from the groupconsisting of C₄-alk(en)lyene, N(CH)₃, CHN(CH)₂, N(CH)₂N, N═NCH═N andNCHNCH;

[0043]  wherein said moieties are optionally substituted with halogen,—CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, substituted or unsubstituted phenyl,hydroxy, C₁-C₄alkoxy, SH, C₁-C₄thioalkyl, NH₂, NH(C₁-C₄alkyl) orN(C₁-C₄alkyl)₂;

[0044] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN; and

[0045] provided that

[0046] if Y² is N, then J is a bond and Z¹ is not CE³;

[0047] if Y² is CE¹ and Z¹ is CE³, then J is a bond;

[0048] if Y² is not CE¹ and Z¹ is not CE³, then J is not CE²;

[0049] if J is CE²,

[0050]  then

[0051] Y² is CE¹ and Z¹ is not CE³, CR⁷ or CHR⁷; or

[0052] Z¹ is CE² and Y² is not CE¹, CR⁵ or CHR⁵.

[0053] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is phenyl or 3-pyridyland is substituted with two to three of the same or differentsubstitutents selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₆thioalkyl, C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ andCN; said substituents attached at the 2, 4 or 6-positions of said phenylor said 3-pyridyl.

[0054] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is 2-pyridyl and issubstituted with two of the same or different substitutents selectedfrom the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN; said substituentsattached at the 3 and 5-positions of said 2-pyridyl.

[0055] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R¹ is C₁₋₆alkyl orC₁₋₆haloalkyl.

[0056] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R¹ is methyl or trifluoromethyl.

[0057] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is C(D)NR³R⁴.

[0058] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is C(D)NR³R⁴ and D is O.

[0059] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is C(D)NR³R⁴ and D is S.

[0060] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is CH₂NR³R⁴.

[0061] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R is D′-D″(R³)(R⁴), D is abond and D″ is C—OH.

[0062] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is D′-D″(R³)(R⁴), D is abond and D″ is C or CH.

[0063] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R is D′-D″(R³)(R⁴), D is aCH₂ and D″ is C—OH.

[0064] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R is D′-D″(R³)(R⁴), D isCH₂ and D″ is C or CH.

[0065] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R³ and R⁴ are eachindependently selected from the group consisting of H, C₁₋₆alkyl,C₁₋₆haloalkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₁₋₃alkylene-C₁₋₆thioalkyl, —C₂₋₆alkylidene-(C₁₋₄alkoxy)₂,C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,—C₁₋₆alkylene-CN, —C₁₋₆alkylene-heterocyclo and —C₁₋₆alkylene-aryl;wherein said aryl of said —C₁₋₆alkylene-aryl is optionally substitutedwith one to three of the same or different substituents selected fromthe group consisting of fluoro, chloro, bromo, cyano, nitro, C₁₋₄alkyland C₁₋₃alkoxy.

[0066] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R³ and R⁴ are eachindependently selected from the group consisting of H, C₁₋₆alkyl,C₁₋₆haloalkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₁₋₃alkylene-C₁₋₆thioalkyl, —C₂₋₆alkylidene-(C₁₋₄alkoxy)₂,C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₆alkynyland —C₁₋₆alkylene-CN.

[0067] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R³ and R⁴ together with thenitrogen to which they are attached form a five or six-memberedheterocycle, said heterocycle optionally containing one additionalheteroatom selected from the group consisting of N, S and O; and saidheterocycle optionally substituted with one or more groups selected fromthe group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, aryl, —C₁₋₄alkylene-aryl,pyridyl and halogen; wherein said aryl of said —C₁₋₄alkylene-aryl isoptionally substituted with one to three of the same or differentsubstituents selected from the group consisting of fluoro, chloro,bromo, cyano, nitro and C₁₋₃alkoxy.

[0068] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R³ and R⁴ together with thenitrogen to which they are attached form a five or six-memberedheterocycle, said heterocycle optionally containing one additionalheteroatom selected from the group consisting of N, S and O.

[0069] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R³ and R⁴ together with thenitrogen to which they are attached form a five or six-memberedheterocycle.

[0070] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein J is a bond.

[0071] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹ and Z¹ is CE³.

[0072] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹ and Z¹ is CE³.

[0073] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein J is CE².

[0074] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is substituted 3-pyridyl.

[0075] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is substituted phenyl.

[0076] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is 2, 4,6-trimethylphenyl.

[0077] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein V is 2,4-dichlorophenyl.

[0078] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, benzyl, phenyl, C₁₋₃alkyl-imidazolyl, C₁₋₃alkyl-indolyland C₁₋₃alkyl-pyridyl.

[0079] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH₂, J is a bond andZ¹ is CH₂.

[0080] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH, J is a bond andZ¹ is CH.

[0081] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CR⁵, J is a bond andZ¹ is CH wherein said R⁵ is halo.

[0082] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH, J is a bond andZ¹ is CR⁷ wherein said R⁷ is halo.

[0083] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH, J is a bond andZ¹ is CR⁷ wherein said R⁷ is halo, cyano or C₁₋₆alkyl.

[0084] According to another embodiment of the first aspect of thepresent invention are-provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is C(O), J is a bond andZ¹ is CH₂.

[0085] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH₂, J is a bond andZ¹ is C(O).

[0086] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² isCH₂, J is a bond, Z¹ is CH₂, Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0087] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CH₂,J is a bond, Z¹ is CH₂, Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0088] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CH₂,J is a bond, Z¹ is CH₂, Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0089] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CH₂,J is a bond, Z¹ is CH₂, Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0090] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein Y² isCH₂, J is CH₂ and Z¹ is CH₂.

[0091] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ is CNor CF₃ and Y² is CH₂, J is CH₂ and Z¹ is CH₂.

[0092] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is C(O), J is CH and Z¹is CH.

[0093] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CH, J is CH and Z¹ isC(O).

[0094] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is C(O), J is CE² and Z¹is CE³ wherein E² and E³ together form C₄-alk(en)lyene optionallysubstituted with halogen.

[0095] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹, J is CE² and Z¹is C(O) wherein E¹ and E² together form C₄-alk(en)lyene optionallysubstituted with halogen.

[0096] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is C(O), J is CE and Z¹is CE³ wherein E² and E³ together form N(CH)₃, CHN(CH)₂, N(CH)₂N,N═NCH═N or NCHNCH optionally substituted with halogen.

[0097] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹, J is CE² and Z¹is C(O) wherein E¹ and E² together form N(CH)₃, CHN(CH)₂, N(CH)₂N,N═NCH═N or NCHNCH optionally substituted with halogen.

[0098] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹, J is a bond, Z¹is CE³ wherein E¹ and E³ together form C₄-alk(en)lyene optionallysubstituted with halogen.

[0099] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹, J is a bond, Z¹is CE³ wherein E¹ and E³ together form N(CH)₃ optionally substitutedwith halogen, methoxy, methyl or nitrile.

[0100] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein R² is CH₂NR³R⁴, R³ is ethylor propyl, R⁴ is —CH₂)₂-phenyl, Y² is CE¹, J is a bond, Z¹ is CE³wherein E¹ and E³ together form N(CH)₃ optionally substituted withhalogen, methoxy, methyl or nitrile.

[0101] According to another embodiment of the first aspect of thepresent invention are provided compounds of Formula (I) according to thefirst embodiment of the first aspect wherein Y² is CE¹, J is a bond, Z¹is CE³ wherein E¹ and E³ together form N(CH)₃, CHN(CH)₂, N(CH)₂N,N═NCH═N or NCHNCH optionally substituted with halogen.

[0102] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² isCE¹, J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═C(F)CH═CH—, Zis N—V and V is 2,4,6-trimethyl-phenyl.

[0103] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is LCH₂-cyclopropyl, Y² isCE¹, J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—, Z isN—V and V is 2,4,6-trimethyl-phenyl.

[0104] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0105] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ istrifluoromethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl,Y² is CE¹, J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—,Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0106] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² isCE¹, J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—, Z isN—V and V is 2,4-dichloro-phenyl.

[0107] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is C(O)NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z, is CE³, E¹ and E³ together form —CH═C(F)CH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0108] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z, is CE³, E¹ and E³ together form —CH═C(F)CH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0109] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ ismethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0110] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═CHCH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0111] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ istrifluoromethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl,Y² is CE¹, J is a bond, Z, is CE³, E¹ and E³ together form —CH═CHCH═CH—,Z is N—V and V is 2,4,6-trimethyl-phenyl.

[0112] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein R¹ isethyl, R² is CH₂NR³R⁴, R³ is propyl, R⁴ is —CH₂-cyclopropyl, Y² is CE¹,J is a bond, Z¹ is CE³, E¹ and E³ together form —CH═C(F)CH═CH—, Z is N—Vand V is 2,4,6-trimethyl-phenyl.

[0113] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein “aryl”or “ar-” is phenyl or napthalenyl.

[0114] According to another embodiment of the first aspect of thepresent invention is provided a compound of Formula (I) wherein“heterocyclic” or “heterocyclo” is furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzthiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl, azetidinyl, piperidyl,piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl,morpholinyl, thiomorpholinyl or tetrahydropyranyl.

[0115] According to another embodiment of the first aspect of thepresent invention are compounds of Formula (I) and salts or solvatesthereof selected from the group consisting of2-methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide,2-ethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide,5-fluoro-2-methyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,2-methyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,2-ethyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,2-trifluoromethyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,8-(2,4-dichlorophenyl)-2-methyl-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,2-ethyl-5-fluoro-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide,cyclopropylmethyl-[5-fluoro-2-methyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine,cyclopropylmethyl-[2-methyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine,cyclopropylmethyl-[2-ethyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine,cyclopropylmethyl-propyl-(2-trifluoromethyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl)-amineandcyclopropylmethyl-[2-ethyl-5-fluoro-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine.

[0116] According to another embodiment of the first aspect of thepresent invention are compounds of Formula (I) and salts or solvatesthereof selected from the group consisting ofCyclopropylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,

[0117]Cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethylphenyl-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-amine,

[0118]Ethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-phenethyl-amine,

[0119]Cyclobutylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,

[0120][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-phenethyl-propyl-amine,

[0121][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-propyl-amine,

[0122][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-ethyl-phenethyl-amine,

[0123]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(3-phenyl-pyrrolidin-1-ylmethyl)-8H-1,3a,7,8-tetraaza-cyclopenta[x]indene,

[0124]6-Chloro-2-ethyl-7-(2,4-dichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N,N-dipropylamide,

[0125]3-[(N,N-Dipropylamino)methyl]-6-chloro-2-ethyl-7-(2,4-diclorophenyl)-7H-imidazo[1,2-a]imidazole,

[0126]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-ethylamide,

[0127]3-[(N-Cyclopropylmethyl-N-ethylamino)methyl]-6-chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole,

[0128]6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amine,

[0129]6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amine,

[0130][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-ethyl-amine,

[0131][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-amine,

[0132][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-(3,3,3-trifluoro-propyl)-amine,

[0133][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-phenethyl-amine,

[0134][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(3,3,3-trifluoro-propyl)-amine,and

[0135][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-amine.

[0136] According to various embodiments of a second aspect of thepresent invention are provided pharmaceutical compositions comprisingcompounds of Formula (I) as defined herein.

[0137] According to various embodiments of a second aspect of thepresent invention are provided methods of treating depression, anxiety,affective disorders, post-traumatic stress disorder, post-operativestress, headache, drug addiction, eating disorders and obesity, suddendeath due to cardiac disorders, iritable bowel syndrome, hypertension,syndrome X, inflammatory disorders, stress-induced immune suppression,infertility, stress-induced insomnia and other sleep disorders,seizures, epilepsy, stroke and cerebral ischemia, traumatic braininjury, yet other disorders requiring neuroprotection, drug or alcoholwithdrawal symptoms, other disorders including tachycardia, congestiveheart failure, osteoporosis, premature birth, psychosocial dwarfism,ulcers, diarrhea, post-operative ileus and yet other conditions thetreatment of which can be effected by the antagonism of the CRF-1receptor by the administration of pharmaceutical compositions comprisingcompounds of the present invention as described herein.

[0138] According to a first embodiment of a third aspect of the presentinvention are provided compounds of

[0139] Formula (WHH)

[0140] wherein

[0141] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0142] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0143] X is C;

[0144] Y is C;

[0145] X¹ is N;

[0146] Y¹ is N;

[0147] Y² is CH₂;

[0148] J is CH₂ or a bond;

[0149] Z¹ is CH₂ or C(O); and

[0150] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN.

[0151] According to another embodiment of a third aspect of the presentinvention are provided processes for preparing compounds of Formula(WHH)

[0152] wherein

[0153] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0154] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0155] X is C;

[0156] Y is C;

[0157] X¹ is N;

[0158] Y¹ is N;

[0159] Y² is CH₂;

[0160] J is CH₂ or a bond;

[0161] Z¹ is CH₂ or C(O); and

[0162] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN;

[0163] comprising reacting a compound of Formula (UFF)

[0164] wherein

[0165] Z, Z¹, J and Y² are defined as for Formula (WHH);

[0166] with a compound of Formula (UFF′)

[0167] wherein

[0168] R¹, R⁸, X, Y, X¹ and Y¹ are defined as for Formula (WHH);

[0169] in the presence of a suitable base and polar aprotic solvent toyield a compound of Formula (VGG)

[0170] wherein

[0171] R¹, R⁸, X, Y, X¹, Y¹, Y², J, Z¹ and Z are defined as for Formula(WHH);

[0172] and reacting said compound of Formula (VGG) with a high-boilingpoint polar aprotic solvent and a suitable silver salt under suitablyhigh temperature.

[0173] According to another embodiment of a third aspect of the presentinvention are provided compounds of Formula (Z′)

[0174] wherein

[0175] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0176] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0177] X is C;

[0178] Y is C;

[0179] X¹ is N;

[0180] Y¹ is N;

[0181] Y² is CH or CR⁵;

[0182] R⁵ is selected from the group consisting of —CN,—C₁₋₄-alk(en)ylene-CN, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,C₁₋₆haloalkyl, aryl, —C₁₋₄alk(en)ylene-aryl,—C₁₋₄alk(en)ylene-heterocyclo, heterocyclo, —C₁₋₄alk(en)ylene-amino,—C₁₋₄alkylene-amino-C₁₋₄alkyl, aryl-amino, -amino-(C₁₋₆alk(en)yl)₁₋₂,-amino-aryl, -amino-heterocyclo, C₁₋₆alkoxy, —O-aryl and —O-heterocyclo;

[0183] Z¹ is C(O); and

[0184] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN.

[0185] According to another embodiment of a third aspect of the presentinvention are provided processes for preparing compounds of Formula (Z′)

[0186] wherein

[0187] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0188] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0189] X is C;

[0190] Y is C;

[0191] X¹ is N;

[0192] Y¹ is N;

[0193] Y² is CH or CR⁵;

[0194] R⁵ is selected from the group consisting of —CN,—C₁₋₄-alk(en)ylene-CN, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,C₁₋₆haloalkyl, aryl, —C₁₋₄alk(en)ylene-aryl,—C₁₋₄alk(en)ylene-heterocyclo, heterocyclo, —C₁₋₄alk(en)ylene-amino,—C₁₋₄alkylene-amino-C₁₋₄alkyl, aryl-amino, -amino-(C₁₋₆alk(en)yl)₁₋₂,-amino-aryl, -amino-heterocyclo, C₁₋₆alkoxy, —O-aryl and —O-heterocyclo;

[0195] Z¹ is C(O); and

[0196] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN;

[0197] comprising reacting a compound of Formula (X′)

[0198] wherein

[0199] Z, Z¹ and Y² are defined as for Formula (Z′);

[0200] with a compound of Formula (UFF′)

[0201] wherein

[0202] R¹, R⁸, X, Y, X¹ and Y¹ are defined as for Formula (Z′);

[0203] in the presence of a suitable base and polar aprotic solvent toyield a compound of Formula (Y′)

[0204] wherein

[0205] R¹, R⁸, X, Y, X¹, Y¹, Y² Z¹ and Z are defined as for Formula(Z′);

[0206] and reacting said compound of Formula (Y′) with a high-boilingpoint polar aprotic solvent and a suitable silver salt under suitablyhigh temperature.

[0207] According to another embodiment of a third aspect of the presentinvention are provided compounds of Formula (AA′)

[0208] wherein

[0209] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0210] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0211] X is C;

[0212] Y is C;

[0213] X¹ is N;

[0214] Y¹ is N;

[0215] Y² is CH or CR⁵;

[0216] R⁵ is selected from the group consisting of —CN,—C₁₋₄-alk(en)ylene-CN, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,C₁₋₆haloalkyl, aryl, —C₁₋₄alk(en)ylene-aryl,—C₁₋₄alk(en)ylene-heterocyclo, heterocyclo, —C₁₋₄alk(en)ylene-amino,—C₁₋₄alkylene-amino-C₁₋₄alkyl, aryl-amino, -amino-(C₁₋₆alk(en)yl)₁₋₂,-amino-aryl, -amino-heterocyclo, C₁₋₆alkoxy, —O-aryl and —O-heterocyclo;

[0217] Z¹ is CR⁷;

[0218] wherein R⁷ is chloro or bromo; and

[0219] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN.

[0220] According to another embodiment of a third aspect of the presentinvention are provided processes for preparing compounds of Formula(AA′)

[0221] wherein

[0222] R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,cyano, halo, C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenylor C₃₋₆alkynyl;

[0223] R⁸ is O—C₁₋₄alkyl, —N(CH₃)(OCH₃) or other suitable leaving group;

[0224] X is C;

[0225] Y is C;

[0226] X¹ is N;

[0227] Y¹ is N;

[0228] Y² is CH or CR⁵;

[0229] R⁵ is selected from the group consisting of —CN, —C₁₋₄alk(en)ylene-CN, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,C₁₋₆haloalkyl, aryl, —C₁₋₄alk(en)ylene-aryl,—C₁₋₄alk(en)ylene-heterocyclo, heterocyclo, —C₁₋₄alk(en)ylene-amino,—C₁₋₄alkylene-amino-C₁₋₄alkyl, aryl-amino, -amino-(C₁₋₆alk(en)yl)₁₋₂,-amino-aryl, -amino-heterocyclo, C₁₋₆alkoxy, —O-aryl and —O-heterocyclo;

[0230] Z¹ is CR⁷;

[0231] wherein R⁷ is chloro or bromo; and

[0232] Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substitutedwith two to three of the same or different substitutents selected fromthe group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN;

[0233] comprising reacting a compound of Formula (Z′)

[0234] wherein

[0235] R¹, R⁸ X, Y, X¹, Y¹, Y², and Z are defined as for Formula (AA′);and

[0236] Z¹ is C(O);

[0237] with phosphoryl trichloride or phosphoryl tribromide, neat orwith a suitable solvent and without a base or with a suitable base.

[0238] Other embodiments of the present invention may comprise asuitable combination of two or more of the embodiments and/or aspectsdisclosed herein.

[0239] Yet other embodiments and aspects of the invention will beapparent according to the description provided below.

DETAILED DESCRIPTION OF THE INVENTION

[0240] The description of the invention herein should be construed incongruity with the laws and principals of chemical bonding. Anembodiment or aspect which depends from another embodiment or aspect,will describe only the variables having values and provisos that differfrom the embodiment or aspect from which it depends.

[0241] As used herein, “aryl” or “ar-” includes phenyl or napthalenyl.

[0242] As used herein, “heterocyclic” or “heterocyclo” includes bothheteroaryl and heteroalicyclic. “Heteroaryl” includes but is not limitedto furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, benzthiazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl,pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl,carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl orpyrazinyl. “Heteroalicyclic” includes but is not limited to azetidinyl,piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl,morpholinyl, thiomorpholinyl or tetrahydropyranyl. “Heteroalicyclic”further includes moieties otherwise heteroaromatic but for the additionof one or more hydrogen atoms, e.g., dihydropyridine.

[0243] As used herein, “halo” or “halogen” includes fluoro, chloro,bromo and iodo and further means one or more of the same or differenthalogens may be substituted on a respective moiety.

[0244] Unless specificied otherwise, alkyl, alkenyl and alkynyl may bebranched or straight chained. As used herein, “alk(en)yl” or“alk(en)ylene” includes alkyl or alkenyl groups. Alkenyl and alkynylgroups may contain one or more double or triple bonds respectively.Where a range of carbon atoms is designated, e.g., C-₁₋₄alk(en)ylene,alkenyl groups it is understood that according to the principals ofchemical bonding must have at least two carbons in length.

[0245] It is to be understood that the present invention may include anyand all possible stereoisomers, geometric isomers, diastereoisomers,enantiomers, anomers and optical isomers, unless a particulardescription specifies otherwise.

[0246] The compounds of this invention may exist in the form ofpharmaceutically acceptable salts. Such salts may include addition saltswith inorganic acids such as, for example, hydrochloric acid andsulfuric acid, and with organic acids such as, for example, acetic acid,citric acid, methanesulfonic acid, toluenesulfonic acid, tartaric acidand maleic acid. Further, in case the compounds of this inventioncontain an acidic group, the acidic group may exist in the form ofalkali metal salts such as, for example, a potassium salt and a sodiumsalt; alkaline earth metal salts such as, for example, a magnesium saltand a calcium salt; and salts with organic bases such as atriethylammonium salt and an arginine salt. The compounds of the presentinvention may be hydrated or non-hydrated.

[0247] The compounds of this invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups and emulsions. The compounds ofthis invention may also be administered intravenously,intraperitoneally, subcutaneously, or intramuscularly, all using dosageforms well known to those skilled in the pharmaceutical arts.

[0248] The compounds can be administered alone, but generally will beadministered with a pharmaceutical carrier selected upon the basis ofthe chosen route of administration and standard pharmaceutical practice.Compounds of this invention can also be administered in intranasal formby topical use of suitable intranasal vehicles, or by transdermalroutes, using transdermal skin patches. When compounds of this inventionare administered transdermally the dosage will be continuous throughoutthe dosage regimen.

[0249] Compounds of the present invention may be used for the treatmentof a variety of conditions including depression, anxiety, affectivedisorders, eating disorders and obesity (see Peripheral administrationof CRF and urocortin: effects on food intake and the HPA axis in themarsupial Sminthopsis crassicaudata. Hope, P. J.; Tumbull, H.; Farr, S.;Morley, J. E.; Rice, K. C.; Chrousos, G. P.; Torpy, D. J.; Wittert, G.A. Department of Medicine, University of Adelaide, Royal AdelaideHospital, South Australia, Australia. Peptides (N.Y.) (2000), 21(5),669-677), sudden death due to cardiac disorders (see Use ofcorticotropin releasing factor (CRF) antagonists to prevent suddendeath. Fossa, Anthony Andrea. (Pfizer Products Inc., USA). Eur. Pat.Appl. (2000), EP 1040831 A2), post-traumatic stress disorder, headache,post-operative stress (see WO 0158489 A1), drug addiction, iritablebowel syndrome (see Stress and the gastrointestinal tract III.Stress-related alterations of gut motor function: role of braincorticotropin-releasing factor receptors. Tache Y; Martinez V; MillionM; Wang L CURE: Digestive Diseases Research Center, Department ofVeterans Affairs Greater Los Angeles Healthcare System, Bldg. 115, Rm.203, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, USA. AMERICANJOURNAL OF PHYSIOLOGY. GASTROINTESTINAL AND LIVER PHYSIOLOGY (2001 Feb),280(2), G173-7; Role of CRF receptor 1 in central CRF-inducedstimulation of colonic propulsion in rats. Martinez, V.; Tache, Y.Digestive Disease Division and Brain Research Institute, Department ofMedicine, CURE: Digestive Diseases Research Center, VeteransAdministration Greater Los Angeles Healthcare System, University ofCalifornia at Los Angeles, Los Angeles, Calif., USA. Brain Res. (2001),893(1,2), 29-35; and Peripheral corticotropin-releasing factor andstress-stimulated colonic motor activity involve type 1 receptor inrats. Maillot, Celine; Million, Mulugeta; Wei, Jen Yu; Gauthier, Ariane;Tache, Yvette. Digestive Diseases Research Center, Va. Greater LosAngeles Healthcare System, Department of Medicine, Division of DigestiveDiseases, and Brain Research Institute, University of California Schoolof Medicine, Los Angeles, Calif., USA. Gastroenterology (2000), 119(6),1569-1579), hypertension (see Combinations of CRF antagonists andrenin-angiotensin system inhibitors. Fossa, Anthony Andrea. (PfizerProducts Inc., USA). Eur. Pat. Appl. (2000), 21 pp. and Antalarminblockade of corticotropin releasing hormone-induced hypertension inrats. Briscoe, R. J.; Cabrera, C. L.; Baird, T. J.; Rice, K. C.; Woods,J. H. Department of Pharmacology, University of Michigan, Ann Arbor,Mich., USA. Brain Res. (2000), 881(2), 204-207), syndrome X (also knownas metabolic syndrome, plurimetabolic syndrome or insulin resistancesyndrome) (see EP1 097 709 A2), inflammatory disorders andstress-induced immune suppression (see Stress, corticotropin-releasinghormone, glucocorticoids, and the immune/inflammatory response: acuteand chronic effects. Elenkov, Ilia J.; Webster, Elizabeth L.; Torpy,David J.; Chrousos, George P. Pediatric Endocrinology Section,Developmental Endocrinology Branch, National Institute of Child Healthand Human Development, and Inflammatory Joint Diseases Section,Arthritis and Rheumatism Branch, National Institute of Arthritis andMusculoskeletal and Skin Diseases, National Institutes of Health,Bethesda, Md., USA. Ann. N.Y. Acad. Sci. (1999), 876(NeuroendocrineImmune Basis of the Rheumatic Diseases), 1-13; Corticotropin-releasinghormone and inflammation. Webster, Elizabeth L.; Torpy, David J.;Elenkov, Ilia J.; Chrousos, George P. Pediatric Endocrinology Section,Developmental Endocrinology Branch, National Institute of Child Healthand Development, National Institutes of Health, Bethesda, Md., USA. Ann.N.Y. Acad. Sci. (1998), 840(Neuroimmunomodulation), 21-32; andPeripheral corticotropin-releasing factor mediates the elevation ofplasma IL-6 by immobilization stress in rats. Ando T; Rivier J;Yanaihara H; Arimura A United States-Japan Biomedical ResearchLaboratories, Tulane University Hebert Center, Belle Chasse, La.70037-3001, USA AMERICAN JOURNAL OF PHYSIOLOGY (1998 Nov), 275(5 Pt 2),R1461-7), infertility (see Corticotropin-releasing factor (CRF) andstress-related reproductive failure: The brain as a state of the art orthe ovary as a novel clue? Nappi, R. E.; Rivest, S. CHUL ResearchCenter, Laval University, PQ, Can. J. Endocrinol. Invest. (1995),18(11), 872-80)), stress-induced insomnia and other sleep disorders (seeUse of CRF antagonists and related compositions for modifying circadianrhythm and treatment of depression and other conditions. Chen, YuhpyngLiang. (Pfizer Products Inc., USA). Eur. Pat. Appl. (2001), 29 pp EP1082960 A2; Middle-Aged Men Show Higher Sensitivity of Sleep to theArousing Effects of Corticotropin-Releasing Hormone Than Young Men:Clinical Implications. Vgontzas A N, Bixler E O, Wittman A M, Zachman K,Lin H M, Vela-Bueno A, Kales A, Chrousos G P. Sleep Research andTreatment Center, Department of Psychiatry and Department of HealthEvaluation Sciences (H.-M.L.), Pennsylvania State University, Hershey,Pa. 17033. J. Clin. Endocrinol. Metab. (2001), 86 (4): 1489-1495; IL-1is a mediator of increases in slow-wave sleep induced by CRH receptorblockade. Chang, Fang-Chia; Opp, Mark R. Neuroscience Graduate Program,University of Texas Medical Branch, Galveston, Tex., USA. Am. J.Physiol. (2000), 279(3, Pt. 2), R793-R802; Blockade ofcorticotropin-releasing hormone receptors reduces spontaneous waking inthe rat. Chang, Fang-Chia; Opp, Mark R. Neuroscience Graduate Program,University of Texas Medical Branch, Galveston, Tex., USA. Am. J.Physiol. (1998), 275(3, Pt. 2), R793-R802; Non-peptidiccorticotropin-releasing hormone receptor type 1 antagonist reversesrestraint stress-induced shortening of sodium pentobarbital-inducedsleeping time of rats: evidence that an increase in arousal induced bystress is mediated through CRH receptor type 1. Arai, Keiko; Ohata,Hisayuki; Shibasaki, Tamotsu. Department of Physiology, Nippon MedicalSchool, Tokyo, Japan. Neurosci. Lett. (1998), 255(2), 103-106; Ratstrain differences suggest a role for corticotropin-releasing hormone inmodulating sleep. Opp, Mark R. Department of Psychiatry and BehavioralSciences, University of Texas Medical Branch, Galveston, Tex., USA.Physiol. Behav. (1997), Volume Date 1998, 63(1), 67-74), seizures (seeThe effect of ‘Astressin’, a novel antagonist of corticotropin releasinghormone (CRH), on —CRH-induced seizures in the infant rat: comparisonwith two other antagonists. Baram T Z; Koutsoukos Y; Schultz L; Rivier JDepartment of Pediatrics, University of California, Irvine 92717, USAMOLECULAR PSYCHIATRY (1996 Jul), 1(3), 223-6; and Astressin, a novel andpotent CRF antagonist, is neuroprotective in the hippocampus whenadministered after a seizure. Maecker H; Desai A; Dash R; Rivier J; ValeW; Sapolsky R Department of Biological Sciences, Stanford University, CA94305, USA BRAIN RESEARCH (1997 Jan 2), 744(1), 166-70), epilepsy (seeInfantile spasms. Hypothesis-driven therapy and pilot human infantexperiments using corticotropin-releasing hormone receptor antagonists.Baram, Tallie Z.; Mitchell, Wendy G.; Brunson, Kristen; Haden,Elizabeth. Department Anatomy/Neurobiology, Univ. California Irvine,Irvine, Calif., USA. Dev. Neurosci. (Basel) (1999), 21(3-5), 281-289;and The pro-convulsant actions of corticotropin-releasing hormone in thehippocampus of infant rats. Hollrigel, G. S.; Chen, K.; Baram, T. Z.;Soltesz, I. Department of Anatomy and Neurobiology, University ofCalifornia, Irvine, Calif., USA. Neuroscience (Oxford) (1998), 84(1),71-79), stroke and cerebral ischemia (see Neuroprotection bycorticotropin releasing factor during hypoxia in rat brain. Fox M W;Anderson R E; Meyer F B Department of Neurosurgery, Mayo Clinic,Rochester, Minn. 55905. STROKE (1993 Jul), 24(7), 1072-5; discussion1075-6; Neuroprotective effects of corticotropin-releasing factorreceptor antagonists. Loddick, S. A.; Chalmers, D. T.; Yatsushiro, K.;McCulloch, J.; Foster, A. C.; Rothwell, N.J.; De Souza, E. B. NeurocrineBiosciences, Inc., San Diego, Calif., USA. Editor(s): Krieglstein,Josef. Pharmacol. Cereb. Ischemia 1998, [Int. Symp.], 7th (1999),Meeting Date 1998, 371-378. Publisher: Medpharm Scientific Publishers,Stuttgart, Germany CODEN: 680ZA5 Conference; Corticotropin releasingfactor antagonist reduces ischemic hippocampal neuronal injury. Lyons,Mark K.; Anderson, Robert E.; Meyer, Fredric B. Mayo Clin., Mayo Grad.Sch. Med., Rochester, Minn., USA. Brain Res. (1991), 545(1-2), 339-42;Focal cerebral ischemia induces CRH mRNA in rat cerebral cortex andamygdala. Wong M L; Loddick S A; Bongiomo P B; Gold P W; Rothwell N J;Licinio J Clinical Neuroendocrinology Branch, NIMH, NIH, Bethesda, Md.20892-1284, USA NEUROREPORT (1995 Sep 11), 6(13), 1785-8; ) traumaticbrain injury (see Evidence for the involvement ofcorticotrophin-releasing hormone in the pathogenesis of traumatic braininjury. Roe S Y; McGowan E M; Rothwell N J School of BiologicalSciences, University of Manchester, UK EUROPEAN JOURNAL OF NEUROSCIENCE(1998 Feb), 10(2), 553-9; The effects of human corticotrophin releasingfactor on motor and cognitive deficits after impact acceleration injury.Beaumont, Andrew; Marmarou, Christina; Marmarou, Anthony. Division ofNeurosurgery, Department of Physiology, Medical College of Virginia,Richmond, Va., USA. Neurol. Res. (2000), 22(7), 665-673) and yet otherdisorders requiring neuroprotection, drug or alcohol withdrawalsymptoms, other disorders including tachycardia, congestive heartfailure, osteoporosis, premature birth, psychosocial dwarfism, ulcer,diarrhea and post-operative ileus (see New uses for heterocycliccorticotropin-releasing factor (CRF) antagonists in treatingcardiovascular diseases, osteoporosis, ulcers, and other disorders.Chen, Yuhpyng Liang; Fossa, Anthony Andrea. (Pfizer Inc., USA). Eur.Pat. Appl. (1997), 15 pp. EP 773023 A1) and yet other conditions thetreatment of which can be effected by the antagonism of the CRF-1receptor by the administration of pharmaceutical compositions comprisingcompounds of the present invention as described herein.

[0250] The dosage and dosage regimen and scheduling of a compounds ofthe present invention must in each case be carefully adjusted, utilizingsound professional judgment and considering the age, weight andcondition of the recipient, the route of administration and the natureand extent of the disease condition. In accordance with good clinicalpractice, it is preferred to administer the instant compounds at aconcentration level which will produce effective beneficial effectswithout causing any harmful or untoward side effects.

[0251] Compounds of the present invention may be synthesized accordingto the general schemes provided below. Variables corresponding tocompounds of Formula (I) have been introduced in the schemes below atparticular instances to further depict how said compounds may besynthesized. Variables provided in the schemes below are defined inaccordance with the description of compounds of Formula (I) unlessotherwise specified. Where a variable has been further defined in anyone scheme below, said variable should assume the same values insubsequent schemes unless yet further defined. The definitions ofcompounds in the schemes below are not intended to narrow the scope ofcompounds described by Formula (I). Moreover, the schemes providedherein may be modified in a manner apparent to one skilled in the art todescribe additional processes for making compounds of the presentinvention.

[0252] Other suitable means of synthesizing said compounds may also beavailable. More detailed descriptions of synthesizing compounds of thepresent invention are also provided as follows:

[0253] General. ¹H and ¹³C NMR spectra in CDCl₃ were run on a Bruker 500or 300 MHz instrument and chemical shifts were reported in ppm (δ) withreference to (CH₃)₄Si. All evaporations were carried out under reducedpressure. Unless otherwise stated, LC/MS analyses were carried out on aShimadzu instrument using a YMC C18 column (3×50 mm) employing a 2 minlinear gradient of 0% to 110% solvent B in A in a 3 min run. For LC/MSand for Shimadzu Preparative HPLC system, Solvent A-was: 10%methanol/90% water/0.1% trifluoroacetic acid, and solvent B was 90%methanol/10% water/0.1% trifluoroacetic acid with a UV detector set at220 nm.

[0254] The following Intermediates 1-5 may be used to synthesizeExamples 1-26.

[0255] Intermediate 1

[0256] N¹-(2,4,6-Trimethyl-phenyl)-ethane-1,2-diamine, scheme 3: (M)

[0257] To a solution of 2,4,6-trimethylaniline (100. g, 0.740 mol) inanhydrous toluene (600 mL) was added 2-bromoethylamine hydrobromide(75.8 g, 0.370 mol). The flask containing the reaction mixture wasfitted with a Dean-Stark trap/reflux condenser assembly. The reactionmixture was heated at reflux temperature for 5 h, during which time themixture solidified. Upon cooling to room temperature, the solidifiedmass was treated with water (240 mL), toluene (160 mL), and 50% aqueousKOH (80 mL). The phases were separated, and the aqueous portion wassaturated with NaCl and extracted with toluene

[0258] (2×200 mL). The combined organic portions were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to remove the solvent. Vacuum distillation (2 mm Hg) afforded42.4 g of a light yellow liquid, which was 92% pure based on ¹H NMR.Eight percent of the material was unreacted 2,4,6-trimethylaniline. ¹HNMR (CDCl₃, 300 MHz) δ 6.83 (s, 2H), 3.00-2.96 (m, 2H), 2.92-2.88 (m,2H), 2.28 (s, 6H), 2.23 (s, 3H), 2.21 (s, 1H), 2.16 (s, 2H). LC/MS:t_(R)=0.87 min., (MH⁺)=179.19.

[0259] Intermediate 2

[0260] 1-(2,4,6-Trimethyl-phenyl)-4,5-dihydro-1H-imidazol-2-ylamine,scheme 3: (N)¹

[0261] A solution of cyanogen bromide (1.8 g, 18.5 mmol) in anhydrousethanol (3 mL) was added at 0° C. to a solution ofN¹-(2,4,6-trimethyl-phenyl)-ethane-1,2-diamine (3.0 g, 16.9 mmol) inanhydrous ethanol (9 mL) under nitrogen. The reaction mixture was warmedup to room temperature for 10 min, then was heated at 155° C. for 40 minwith a flow of nitrogen to remove ethanol. Upon cooling to r.t., theresulting solids were transferred to a separatory funnel viadichloromethane (70 mL), and washed sequentially with 1 N sodiumhydroxide (2×35 mL), water and brine. The organic layer was dried overanhydrous sodium sulfate and solvents were removed in vacuo to affordthe title compound as a pale white solid (3.08 g, 90% yield). The solidswere used for the next step without further purification.

[0262]¹H NMR (CDCl₃, 300 MHz) δ 6.70 (s, 2H), 3.46 (s, 4H), 2.06 (s,3H), 1.99 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 160.1, 138.2, 137.8, 132.2,129.5, 48.8, 43.5, 20.8, 17.5. LC/MS: t_(R)=0.99 min., (MH⁺)=204.12.

[0263] Intermediate 3

[0264]3-Ethoxycarbonylmethyl-1-(2,4,6-trimethyl-phenyl)-2-aminoimidazoliumbromide, scheme 3: (O)

[0265] To a mixture of1-(2,4,6-trimethyl-phenyl)-imidazolidin-2-ylideneamine (3.00 g, 0.0148mol) and aluminum tri-tert-butoxide (1.0 g, 0.0041 mol) indimethylformamide (15 mL) was added ethyl bromoacetate (1.65 mL, 2.48 g,0.00148 mol). The reaction mixture was allowed to stir at roomtemperature for 1 h, after which LC-MS indicated a 4:1 ratio of desiredproduct to starting material. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure to give a paleorange-yellow solid, which was then treated twice with toluene toazeotropically remove any water. The solid was triturated with toluene,collected by filtration, and placed under high vacuum for 6 h. ¹H NMR(CDCl₃, 300 MHz) δ 7.01 (s, 2H), 4,87 (s, 2H), 4.29 (q, J=7 Hz, 2H),3.96-3.89 (m, 4H), 2.32 (s, 3H), 2.25 (s, 6H), 1.34 (t, J=7 Hz, 3H).LC/MS: t_(R)=0.92 min., (MH⁺)=290.43.

[0266] Intermediate 4

[0267]2-Methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2α]imidazole-3-carboxylicacid ethyl ester, (scheme 3: (P)²

[0268] A mixture of3-ethoxycarbonylmethyl-1-(2,4,6-trimethyl-phenyl)-2-aminoimidazoliumbromide (1.0 g, 2.7 mmol), sodium acetate (0.55 g, 6.75 mmol) and aceticanhydride (5.0 mL) was heated at 160° C. for 12 hr. Upon cooling, themixture was poured into a flask containing ice. While stirring, excesssodium bicarbonate was added to the above mixture in small portions, andthe resulting mixture was stirred at room temperature for 6 hr. Then,the mixture was extracted with dichloromethane (2×40 mL). The organicextracts were washed with water and dried over anhydrous sodium sulfate.Solvents were removed in vacuo and the residue was subjected tochromatography using ethyl acetate/hexanes (1:4) as eluent to afford thetitle compound as a light yellow oil which solidified upon cooling(0.344 g, 41% yield). ¹H NMR (CDCl₃, 300 MHz) δ 6.89 (s, 2H), 4.32 (q,J=7.1 Hz, 2H), 4.36-4.26 (m, 2H), 4.15-4.08 (m, 2H), 2.39 (s, 3H), 2.26(s, 3H), 2.20 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). Mass spec.: 314.15 (MH⁺).

[0269] Intermediate 5

[0270]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid ethyl ester, scheme 3: (P)

[0271] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 6.90 (s, 2H), 4.36 (t, J=8.4 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H),4.14 (t, J=8.4 Hz, 2H), 2.81 (q, J=7.4 Hz, 2H), 2.26 (s, 3H), 2.21 (s,6H), 1.36 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.5 Hz, 3H). LC/MS: t_(R)=1.35min., (MH⁺)=328.19.

EXAMPLE 1

[0272]

[0273]2-Methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (Q)

[0274] A solution of trimethyl aluminum (2.0 M in heptane, 2.2 mL, 4.4mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.63mL, 4.4 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up toroom temperature and stirred at this temperature for 1.5 h, and thenadded to a stirred solution of2-methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (0.172 g, 0.55 mmol) in benzene (8.0 mL). The mixturewas refluxed for 12 h. Upon cooling at 0° C., 1 N sodium hydroxide (25mL) was added dropwise to the above mixture. The mixture was extractedwith dicholoromethane (40 m-L), and the organic layer was dried overanhydrous sodium sulfate. Solvents were removed in vacuo and the residuewas subjected to chromatography using ethyl acetate/hexanes (1:1) aseluent to afford the title compound as a light yellow oil whichsolidified upon cooling (0.209 g, 100% yield). ¹H NMR (CDCl₃, 300 MHz)δ; ¹³C NMR (CDCl₃, 75 MHz) δ 163.1, 156.0, 141.0, 136.5, 136.1, 132.7,128.7, 115.8, 52.6, 50.3, 47.1, 42.1, 20.1, 19.9, 17.3, 14.6, 10.3, 9.2,2.8. Mass spec.: 381.26 (MH⁺).

EXAMPLE 2

[0275]

[0276]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (O)

[0277] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 6.83 (s, 2H), 4.12-4.01 (m, 4H), 3.56 (t, J=7.1 Hz, 2H), 3.35 (d,J=6.8 Hz, 2H), 2.42 (q, J=7.5 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 6H), 1.59(quintet, J=7.2 Hz, 2H), 1.11 (t, J=7.5 Hz, 3H), 0.99-0.95 (m, 1H), 0.86(t, J=7.3 Hz, 3H), 0.51-0.48 (m, 2H), 0.17-0.13 (m, 2H); ¹³C NMR (CDCl₃,75 MHz) δ 164.1, 156.9, 147.6, 137.3, 136.9, 133.9, 129.6, 115.6, 53.6,51.2, 48.1, 42.9, 22.6, 21.0, 20.9, 18.2, 13.7, 11.3, 10.0, 3.75. LC/MS:t_(R)=1.36 min., (MH⁺)=395.27.

EXAMPLE 3

[0278]

[0279]Cyclopropylmethyl-[2-methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazol-3-ylmethyl]-propyl-amine,scheme 3: (R)

[0280] A solution of Red-Al (3.3 M in toluene, 0.70 mL, 2.33 mmol) wasadded dropwise to a solution of2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide (0.177 g, 0.46 mmol) in toluene (3mL) at 0° C. After stirring at room temperature for 24 h, the reactionmixture was cooled to 0° C. and 1 N sodium hydroxide (10 mL) was addeddropwise. The above mixture was extracted with dichloromethane (40 mL),and the organic extracts were washed with water and dried over anhydroussodium sulfate. Solvents were removed in vacuo to afford the titlecompound as a light yellow oil which solidified upon cooling (109 mg,65% yield). The purity of the product was determined to be 91% by LC/MS.¹H NMR (CDCl₃, 300 MHz) δ 6.85 (s, 2H), 4.09-3.96 (m, 4H), 3.45 (s, 2H),2.44 (t, J=7.1 Hz, 2H), 2.29 (d, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.19 (s,6H), 2.04 (s, 3H), 1.46 (quintet, J=7.3 Hz, 2H), 1.28-1.25 (m, 1H), 0.87(t, J=7.2 Hz, 3H), 0.49-0.46 (m, 2H), 0.09-0.06 (m, 2H); ³C NMR (CDCl₃,75 MHz) δ 155.4, 137.1, 136.9, 136.0, 135.0, 129.7, 117.7, 58.5, 55.5,53.8, 48.0, 42.4, 20.9, 20.3, 18.2, 13.3, 12.0, 8.9, 4.0. Mass spec.:367.24 (MH⁺).

EXAMPLE 4

[0281]

[0282]Cyclopropylmethyl-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2α]imidazol-3-ylmethyl]-propyl-amine,scheme 3: (R)

[0283] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 6.86 (s, 2H), 4.13-3.97 (m, 4H), 3.47 (s, 2H), 2.45 (t, J=7.2 Hz,2H), 2.39 (q, J=7.6 Hz, 2H), 2.31 (d, J=6.5 Hz, 2H), 2.24 (s, 3H), 2.19(s, 6H), 1.48-1.42 (m, 2H), 1.32-1.26 (m, 1H), 1.06 (t, J=7.4 Hz, 3H),0.87 (t, J=7.2 Hz, 3H), 0.50-0.46 (m, 2H), 0.09-0.07 (m, 2H). Massspec.: 381.28 (MH⁺).

EXAMPLE 5

[0284]

[0285]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0286] Prepared as described for the example above. LC/MS: t_(R)=1.51min., (MH⁺)=435.36.

EXAMPLE 6

[0287]

[0288]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid propyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (O)

[0289] Prepared as described for the example above. LC/MS: t_(R)=1.25min., (MH⁺)=423.37.

EXAMPLE 7

[0290]

[0291]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(3,3,3,2,2-pentafluoro-propyl)-amide, scheme 3:(O)

[0292] Prepared as described for the example above. LC/MS: t_(R)=1.43min., (MH⁺)=485.35.

EXAMPLE 8

[0293]

[0294]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(cyclopropylmethyl)-amide, scheme 3: (Q)

[0295] Prepared as described for the example above. LC/MS: t_(R)=1.28min., (MH⁺) 407.42.

EXAMPLE 9

[0296]

[0297]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (O)

[0298] Prepared as described for the example above. LC/MS: t_(R)=1.28min., (MH⁺)=449.37.

EXAMPLE 10

[0299]

[0300]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(ethyl)-amide, scheme 3: (O)

[0301] Prepared as described for the example above. LC/MS: t_(R)=1.41min., (MH⁺)=381.36.

EXAMPLE 11

[0302]

[0303]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid dipropyl-amide, scheme 3: (O)

[0304] Prepared as described for the example above. LC/MS: t_(R)=1.26min., (MH⁺)=383.41.

EXAMPLE 12

[0305]

[0306]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid Propyl-(3,3,3-trifluoropropyl)-amide, scheme 3: (O)

[0307] Prepared as described for the example above. LC/MS: t_(R)=1.28min., (MH⁺)=437.33.

EXAMPLE 13

[0308]

[0309]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid phenethyl-propyl-amide, scheme 3: (O)

[0310] Prepared as described for the example above. LC/MS: t_(R)=1.45min., (MH⁺)=445.37.

EXAMPLE 14

[0311]

[0312]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (4-chloro-benzyl)-(3,3,3-trifluoro-propyl)-amide, scheme 3: (Q)

[0313] Prepared as described for the example above. LC/MS: t_(R)=1.48min., (MH⁺)=519.35.

EXAMPLE 15

[0314]

[0315]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid butyl-ethyl-amide, scheme 3: (O)

[0316] Prepared as described for the example above, except thatN-ethylbutylamine was used rather than its HCl salt. LC/MS: t_(R)=1.41min., (MH⁺)=383.37.

EXAMPLE 16

[0317]

[0318]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (2-cyclopropyl-ethyl)-ethyl-amide, scheme 3: (O)

[0319] Prepared as described for the example above. LC/MS: t_(R)=1.38min., (MH⁺)=395.45.

EXAMPLE 17

[0320]

[0321]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (2-cyclopropyl-ethyl)-(3,3,3-trifluoro-propyl)-amide, scheme 3: (O)

[0322] Prepared as described for the example above. LC/MS: t_(R)=1.33min., (MH⁺) 395.45.

EXAMPLE 18

[0323]

[0324]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid benzyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (O)

[0325] Prepared as described for the example above. LC/MS: t_(R)=1.51min., (MH⁺)=485.39.

EXAMPLE 19

[0326]

[0327]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid allyl-propyl-amide, scheme 3: (Q)

[0328] Prepared as described for the example above. LC/MS: t_(R)=1.31min., (MH⁺) 381.36.

EXAMPLE 20

[0329]

[0330]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (2-cyclopropyl-ethyl)-propyl-amide, scheme 3: (O)

[0331] Prepared as described for the example above. LC/MS: t_(R)=1.33min., (MH⁺)=409.43.

EXAMPLE 21

[0332]

[0333]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (4-chloro-benzyl)-propyl-amide, scheme 3: (O)

[0334] Prepared as described for the example above. LC/MS: t_(R)=1.40min., (MH⁺) 465.35.

EXAMPLE 22

[0335]

[0336]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid diallylamide, scheme 3: (O)

[0337] Prepared as described for the example above. LC/MS: t_(R)=1.39min., (MH⁺)=379.40.

EXAMPLE 23

[0338]

[0339]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid phenethyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (O)

[0340] Prepared as described for the example above. LC/MS: t_(R)=1.39min., (MH⁺)=499.38.

EXAMPLE 24

[0341]

[0342]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (3-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amide, scheme 3: (Q)

[0343] Prepared as described for the example above. LC/MS: t_(R)=1.50min., (MH⁺)=503.17.

EXAMPLE 25

[0344]

[0345]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid benzyl-propyl-amide, scheme 3: (O)

[0346] Prepared as described for the example above. LC/MS: t_(R)=1.41min., (MH⁺) 431.34.

EXAMPLE 26

[0347]

[0348]2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid (3-fluoro-benzyl)-propyl-amide, scheme 3: (O)

[0349] Prepared as described for the example above. LC/MS: t_(R)=1.38min., (MH⁺)=449.35.

[0350] The following Intermediates 6-10 may be used to synthesizeExamples 27-29.

[0351] Intermediate 6

[0352] 2-Chloro-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide, scheme 3:(K)

[0353] To a solution of 2-chloro-4,6-dimethylaniline (0.300 g, 0.00193mol) in dichloroethane (6 mL) was added chloroacetic anhydride (0.460 g,0.0027 mol). The reaction was allowed to stir at room temperature for 1h and was then quenched with saturated aqueous NaHCO₃ and allowed tostir for another 15 min. The reaction mixture was extracted with ethylacetate (2×15 mL), and the combined organic portions were washedsequentially with saturated aqueous NaHCO₃ and brine. After drying overanhydrous Na₂SO₄, the organic portion was concentrated under reducedpressure to give 0.40 g (0.0017 mol, 90%) of white solid. ¹H NMR (CDCl₃,300 MHz) δ 7.94 (br s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.25 (s, 2H),2.3 (s, 3H), 2.24 (s, 3H). LC/MS: t_(R)=1.22 min., (MH⁺)=232.02.

[0354] Intermediate 7

[0355] 2-Azido-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide, scheme 3: (L)

[0356] A mixture of 2-Chloro-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide(0.100 g, 0.00043 mol), potassium iodide (0.0072 g, 0.00043 mol), sodiumazide (0.056 g, 0.00086 mol), and anhydrous dimethylformamide (7 mL) washeated in a 50° C. oil bath for 4 h. Upon cooling to room temperature,the reaction mixture was cooled to 0° C., water (10 mL) was added, andthe solid product was collected by suction filtration, washed severaltimes with water, and placed in a vacuum oven set at low heat for 4 h.The dried product amounted to 0.0934 g (0.391 mmol, 91%). ¹H NMR (CDCl₃,300 MHz) δ 7.70 (br s 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.2 (s, 2H), 2.3(s, 3H), 2.23 (s, 3H). LC/MS: t_(R)=1.23 min., (MH⁺)=239.06.

[0357] Intermediate 8

[0358] N¹-(2-Chloro-4,6-dimethyl-phenyl)-ethane-1,2-diamine, scheme 3:(M)

[0359] 2-Azido-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide (0.210 g,0.00126 mol) was dissolved in cold 1.0 M BH₃— tetrahydrofaran (7.6 mL),and the reaction mixture was allowed to stand for approximately 15 min.and was then heated at reflux temperature for 14 h. Upon cooling to roomtemperature, the reaction was quenched with excess methanol, and thesolvents were removed in vacuo. The residue was dissolved in 10 mL 1:1methanol: 10% aqueous HCl and heated at reflux temperature for 3 h. Uponcooling to room temperature, the reaction solution was basified with 2 Naqueous NaOH and extracted with ethyl acetate (3×20 mL). The combinedorganic portions were washed with water and brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to give 0.220 g (0.00111mol, 88%) of pale yellow liquid. ¹H-NMR δ (CDCl₃, 300 MHz) 2.22 (s, 3H),2.29 (s, 3H), 2.86 (t, 2H), 3.06 (t, 2H), 6.84 (d, 1H), 6.99 (d, 1H).LC/MS: t_(R)=1.90 min., (MH⁺)=199.08.

[0360] Intermediate 9

[0361] 1-(2-Chloro-4,6-dimethyl-phenyl)-imidazolidin-2-ylideneamine,scheme 3: (N)

[0362] Prepared as described for1-(2,4,6-trimethyl-phenyl)-imidazolidin-2-ylideneamine. ¹H-NMR δ (CDCl₃,300 MHz) 2.22 (s, 3H), 2.26 (s, 3H), 3.63 (m, 1H), 3.73 (m, 2H), 3.86(m, 1H), 6.07 (br, 2H), 6.96 (s, 1H), 7.08 (s, 1H). LC/MS: t_(R)=0.87min., (MH⁺)=224.15.

[0363] Intermediate 10

[0364]3-Ethoxycarbonylmethyl-1-(2-chloro-4,6-dimethyl-phenyl)-2-aminoimidazoliumbromide, scheme 3: (O)

[0365] Prepared as described for3-ethoxycarbonylmethyl-1-(2,4,6-trimethyl-phenyl)-2-aminoimidazoliumbromide. LC/MS: t_(R)=0.98 min., (MH⁺)=310.17.

[0366] Intermediate 11

[0367]7-(2-Chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 3: (P)

[0368] Prepared as described for2-ethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester. LC/MS: t_(R)=1.33 min., (MH⁺)=348.17.

EXAMPLE 27

[0369]

[0370]7-(2-Chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0371] Prepared as described for2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide. LC/MS: t_(R)=1.36min., (MH⁺)=455.19.

EXAMPLE 28

[0372]

[0373]7-(2-Chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (Q)

[0374] Prepared as described for the example above. LC/MS: t_(R)=1.41min., (MH⁺)=415.24.

EXAMPLE 29

[0375]

[0376]7-(2-Chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2a]imidazole-3-carboxylic acidcyclopropylmethyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (Q)

[0377] Prepared as described for the example above. LC/MS: t_(R)=1.38min., (MH⁺)=469.20.

[0378] The following Intermediates 12-17 may be used to synthesizeExamples 30-33.

[0379] Intermediate 12

[0380] 2-Chloro-N-(2,4-dichloro-6-methyl-phenyl)-acetamide, scheme 3:(K)

[0381] Prepared as described for2-chloro-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide.

[0382] Mass spec.: 253.94 (MH⁺).

[0383] Intermediate 13

[0384] 2-Azido-N-(2,4-dichloro-6-methyl-phenyl)-acetamide, scheme 3: (L)

[0385] Prepared as described for2-azido-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide.

[0386] Intermediate 14

[0387] N¹-(2,4-Dichloro-6-methyl-phenyl)-ethane-1,2-diamine, scheme 3:(M)

[0388] Prepared as described forN¹-(2-chloro-4,6-dimethyl-phenyl)-ethane-1,2-diamine.

[0389]¹H-NMR δ (CDCl₃, 300 MHz) 2.28 (s, 3H), 2.84 (t, 2H), 3.07 (t,2H), 6.98 (d, 1H), 7.15 (d, 1H); Mass spec.: 219.04 (MH⁺).

[0390] Intermediate 15

[0391] 1-(2,4-Dichloro-6-methyl-phenyl)-imidazolidin-2-ylideneamine,scheme 3: (N)

[0392] Prepared as described for1-(2-chloro-4,6-dimethyl-phenyl)-imidazolidin-2-ylideneamine. Massspec.: 244.03 (MH⁺).

[0393] Intermediate 16

[0394]3-Ethoxycarbonylmethyl-1-(2,4-chloro-6-methyl-phenyl)-2-aminoimidazoliumbromide, scheme 3: (O)

[0395] Prepared as described for3-ethoxycarbonylmethyl-1-(2-chloro-4,6-dimethyl-phenyl)-2-aminoimidazoliumbromide. LC/MS: t_(R)=1.12 min., (MH⁺)=410.05.

[0396] Intermediate 17

[0397]7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 3: (P)

[0398] Prepared as described for7-(2-chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester. LC/MS: t_(R)=1.39 min., (MH⁺)=368.16.

EXAMPLE 30

[0399]

[0400]7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (O)

[0401] Prepared as described for7-(2-chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide. LC/MS: t_(R)=1.46min., (MH⁺)=475.19.

EXAMPLE 31

[0402]

[0403]7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (Q)

[0404] Prepared as described for the example above. LC/MS: t_(R)=1.42min., (MH⁺)=435.18.

EXAMPLE 32

[0405]

[0406]7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amide, scheme 3:(O)

[0407] Prepared as described for the example above. LC/MS: t_(R)=1.50min., (MH⁺)=525.13.

EXAMPLE 33

[0408]

[0409]7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid propyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0410] Prepared as described for the example above. LC/MS: t_(R)=1.41min., (MH⁺)=463.19.

[0411] The following Intermediates 18-23 may be used to synthesizeExamples 3440.

[0412] Intermediate 18

[0413] N-(2-Bromo-4-isopropyl-phenyl)-2-chloro-acetamide, scheme 3: (K)

[0414] Prepared as described for2-chloro-N-(2,4-dichloro-6-methyl-phenyl)-acetamide. Mass spec.: 291.97(MH⁺).

[0415] Intermediate 19

[0416] 2-Azido-N-(2-bromo-4-isopropyl-phenyl)-acetamide, scheme 3: (L)

[0417] Prepared as described for2-azido-N-(2,4-dichloro-6-methyl-phenyl)-acetamide.

[0418] Intermediate 20

[0419] N¹-(2-Bromo-4-isopropyl-phenyl)-ethane-1,2-diamine, scheme 3: (M)

[0420] Prepared as described forN¹-(2,4-dichloro-6-methyl-phenyl)-ethane-1,2-diamine. Mass spec.: 270.08(MH⁺).

[0421] Intermediate 21

[0422] 1-(2-Bromo-4-isopropyl-phenyl)-imidazolidin-2-ylideneamine,scheme 3: (N)

[0423] Prepared as described for1-(2,4-dichloro-6-methyl-phenyl)-imidazolidin-2-ylideneamine. Massspec.: 284.09 (MH⁺).

[0424] Intermediate 22

[0425]2-Amino-3-(2-bromo-4-isopropyl-phenyl)-1-ethoxycarbonylmethyl-4,5-dihydro-3H-imidazol-1-ium;bromide, scheme 3: (O)

[0426] Prepared as described for3-ethoxycarbonylmethyl-1-(2,4-chloro-6-methyl-phenyl)-2-aminoimidazoliumbromide. LC/MS: t_(R)=1.29 min., (MH⁺)=368.20.

[0427] Intermediate 23

[0428]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 3: (P)

[0429] Prepared as described for7-(2,4-dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester. LC/MS: t_(R)=1.46 min., (MH⁺)=408.23.

EXAMPLE 34

[0430]

[0431]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0432] Prepared as described for7-(2,4-dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide. LC/MS: t_(R)=1.58min., (MH⁺)=513.15.

EXAMPLE 35

[0433]

[0434]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (Q)

[0435] Prepared as described for the example above. LC/MS: t_(R)=1.47min., (MH⁺)=473.21.

EXAMPLE 36

[0436]

[0437]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid propyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0438] Prepared as described for the example above. LC/MS: t_(R)=1.47min., (MH⁺)=501.02.

EXAMPLE 37

[0439]

[0440]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amide, scheme 3:(Q)

[0441] Prepared as described for the example above. LC/MS: t_(R)=1.61min., (MH⁺)=564.29.

EXAMPLE 38

[0442]

[0443]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclobutylmethyl-propyl-amide, scheme 3: (Q)

[0444] Prepared as described for the example above. LC/MS: t_(R)=1.56min., (MH⁺)=487.21.

EXAMPLE 39

[0445]

[0446]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (Q)

[0447] Prepared as described for the example above. LC/MS: t_(R)=1.51min., (MH⁺)=527.15.

EXAMPLE 40

[0448]

[0449]7-(2-Bromo-4-isopropyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-ethyl-amide, scheme 3: (O)

[0450] Prepared as described for the example above. LC/MS: t_(R)=1.43min., (MH⁺) 459.18.

[0451] The following Intermediates 24-29 may be used to synthesizeExamples 41-49.

[0452] Intermediate 24

[0453] N-(2-bromo-4,6-dimethyl-phenyl)-2-chloro-acetamide, scheme 3: (K)

[0454] Prepared as described for2-chloro-N-(2,4-dichloro-6-methyl-phenyl)-acetamide. Mass spec.: 277.95(MH⁺).

[0455] Intermediate 25

[0456] 2-Azido-N-(2-bromo-4,6-dimethyl-phenyl)-acetamide, scheme 3: (L)

[0457] Prepared as described for2-azido-N-(2,4-dichloro-6-methyl-phenyl)-acetamide.

[0458] Intermediate 26

[0459] N¹-(2-bromo-4,6-dimethyl-phenyl)-ethane-1,2-diamine, scheme 3:(M)

[0460] Prepared as described forN¹-(2,4-dichloro-6-methyl-phenyl)-ethane-1,2-diamine.

[0461]¹H NMR δ (CDCl₃, 300 MHz) 2.22 (s, 3H), 2.31 (s, 3H), 2.87 (t,2H), 3.04 (t, 2H), 6.88 (d, 1H), 7.17 (d, 1H). Mass spec.: 245.11 (MH⁺).

[0462] Intermediate 27

[0463] 1-(2-Bromo-4,6-dimethyl-phenyl)-imidazolidin-2-ylideneamine,scheme 3: (N)

[0464] Prepared as described for1-(2,4-dichloro-6-methyl-phenyl)-imidazolidin-2-ylideneamine. LC/MS:t_(R)=0.91 min., (MH⁺)=270.08.

[0465] Intermediate 28

[0466]2-Amino-3-(2-bromo-4,6-dimethyl-phenyl)-1-ethoxycarbonylmethyl-4,5-dihydro-3H-imidazol-1-iumbromide, scheme 3: (O)

[0467] Prepared as described for3-ethoxycarbonylmethyl-1-(2,4-chloro-6-methyl-phenyl)-2-aminoimidazoliumbromide. LC/MS: t_(R)=1.03 min., (MH⁺)=356.26.

[0468] Intermediate 29

[0469]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 3: (P)

[0470] Prepared as described for7-(2,4-dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester. LC/MS: t_(R)=1.33 min., (MH⁺)=394.31.

EXAMPLE 41

[0471]

[0472]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid phenethyl-propyl-amide, scheme 3: (Q)

[0473] Prepared as described for7-(2,4-dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide. LC/MS: t_(R)=1.42min., (MH⁺)=511.35.

EXAMPLE 42

[0474]

[0475] 7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5Himidazo[1,2-a]imidazole-3-carboxylic acid cyclobutylmethyl-propyl-amide,scheme 3: (Q)

[0476] Prepared as described for the example above. LC/MS: t_(R)=1.68min., (MH⁺) 475.21.

EXAMPLE 43

[0477]

[0478]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclobutylmethyl-ethyl-amide, scheme 3: (Q)

[0479] Prepared as described for the example above. LC/MS: t_(R)=1.58min., (MH⁺)=461.35.

EXAMPLE 44

[0480]

[0481]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amide, scheme 3: (Q)

[0482] Prepared as described for the example above. LC/MS: t_(R)=1.28min., (MH⁺)=501.16.

EXAMPLE 45

[0483]

[0484]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[r1,2-a]imidazole-3-carboxylicacid propyl-(3,3,3-trifluoro-propyl)-amide, scheme 3: (Q)

[0485] Prepared as described for the example above. LC/MS: t_(R)=1.60min., (MH⁺)=503.15.

EXAMPLE 46

[0486]

[0487]7-(2-Bromo-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 3: (Q)

[0488] Prepared as described for the example above. LC/MS: t_(R)=1.56min., (MH⁺) 461.37.

[0489] The following examples 4748 were prepared from Intermediate 5.

EXAMPLE 47

[0490]

[0491]4-[2-Ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol,scheme 11: (DDD)

[0492] To a 0° C. solution of2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (1 mL of a 0.14M solution in toluene) intetrahydrofuran (1 mL) was added n-propylmagnesium chloride (0.84 mL of1.0M in tetrahydrofuran). The resulting solution was removed from theice bath and allowed to stir for 15 min. It was then heated at refluxfor 14h. Upon cooling to room temperature, the reaction solution wasquenched with saturated aqueous ammonium chloride, and the phases wereseparated. The aqueous phase was extracted twice with ether, and thecombined organic portions were washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to give a yellowsemi-solid (0.0448 g, 86%). LC/MS: t_(R)=1.58 min., (MH⁺)=370.31.

EXAMPLE 48

[0493]

[0494]6-Ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazolescheme 11: (EEE)

[0495] A mixture of4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol(0.0444 g, 0.000120 mol) and p-toluenesulfonic acid-H₂O (15 mole %) intoluene (3 mL) was heated at reflux for 1 h. Upon cooling to roomtemperature, the solvent was evaporated under reduced pressure, and theresidue was partitioned between ether and saturated aqueous sodiumbicarbonate. The organic phase was washed with brine, dried overanhydrous Na₂SO₄, and concentrated to give the desired product inquantitative yield. LC-MS indicated the presence of two regioisomers inan approximate ratio of 2:1. LC/MS: t_(R)=1.52 min. and 1.63 min.,(MH⁺)=352.28.

EXAMPLE 49

[0496]

[0497]6-Ethyl-5-(1-propyl-butyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole,scheme 11: (FFF)

[0498]6-Ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole(0.013 g, 0.000037 mol) in anhydrous tetrahydrofaran was treated withcold BH₃-THF (0.15 mL 1.0M in tetrahydrofuran), and the mixture washeated at reflux for 1.5 h. The mixture was cooled to 0° C., treatedwith glacial acetic acid (0.25 mL), heated at reflux for 1.5 h,re-cooled to 0° C., treated with 1.5 mL methanol, and heated again atreflux for 1 h. Upon cooling to room temperature, the reaction mixturewas concentrated under reduced pressure, and the residue was partitionedbetween 2.5 N NaOH and ether. The organic phase was washed with waterand brine, and was then dried over anhydrous Na₂SO₄ and evaporated togive a pale yellow oil. The crude product was chromatographed on silica,eluting with 15% ethyl acetate/hexanes to give a glassy solid. LC/MS:t_(R)=1.81 min., (MH⁺)=354.30.

[0499] The following examples 50-51 were prepared from Intermediates 11and 30.

[0500] Intermediate 30

[0501]4-[7-(2-Chloro-4,6-dimethyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol,scheme 11: (DDD)

[0502] Prepared as described for4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol.The crude product was chromatographed on silica, eluting with 25% ethylacetate/hexanes to afford only one of the possible elimination products.¹H NMR δ (CDCl₃, 300 MHz) 7.12 (s, 1H), 7.03 (s, 1H), 5.59-5.34 (t, 1H),4.33-4.08 (br m, 4H), 2.57-2.38 (q, 2H), 2.33 (s, 3H), 2.26 (s, 3H),2.22-2.15 (t, 2H), 1.74-1.48 (br m, 2H), 1.40-1.33 (q, 2H), 1.25-1.2 (t,3H), 1.08-1.03 (t, 3H), 0.92-0.88 (t, 3H). LC/MS: t_(R)=1.74 min.,(MH⁺)=390.25.

EXAMPLE 50

[0503]

[0504]1-(2-Chloro-4,6-dimethyl-phenyl)-6-ethyl-5-(1-propyl-but-1-enyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole,scheme 11: (EEE)

[0505] Prepared as described for6-ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole.LC/MS: t_(R)=1.74 min., (MH⁺) 372.25.

EXAMPLE 51

[0506]

[0507]1-(2-Chloro-4,6-dimethyl-phenyl)-6-ethyl-5-(1-Propyl-butyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole,scheme 11: (FFF)

[0508] Prepared as described for6-ethyl-5-(1-propyl-butyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole.LC/MS: t_(R)=1.74 min., (MH⁺)=374.21.

[0509] The following Intermediates 17 and 31 were used to prepareExamples 52 and 53. Intermediate 31

[0510]4-[7-(2,4-Dichloro-6-methyl-phenyl)-2-ethyl-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol,scheme 11: (DDD)

[0511] Prepared as described for4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol.LC/MS: t_(R)=1.74 min., (MH⁺)=410.17.

EXAMPLE 52

[0512]

[0513]1-(2,4-Dichloro-6-methyl-phenyl)-6-ethyl-5-(1-propyl-but-1-enyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole,scheme 11: (EEE)

[0514] Prepared as described for6-ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole.LC/MS: t_(R)=1.54 min. and 1.65 min., (MH⁺)=392.18.

EXAMPLE 53

[0515]

[0516]1-(2,4-Dichloro-6-methyl-phenyl)-6-ethyl-5-(1-propyl-butyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole,scheme 11: (FFF)

[0517] Prepared as described for6-ethyl-5-(1-propyl-butyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole.LC/MS: t_(R)=1.68 min., (MH⁺)=394.10.

[0518] The following Intermediates 32-43 may be used to synthesizeExamples 54-55.

[0519] Intermediate 32

[0520] (3-Bromo-propyl)-(2,4,6-trimethyl-phenyl)-amine, scheme 7: (FF)

[0521] To a stirred ice-cold solution of 2,4,6-trimethylaniline (13.5 g,100 mmol) in dioxane (50 mL) under argon was added 1.2 equivalents of1.6 M n-BuLi in hexane drop-wise. The brown mixture was allowed to warmup to room temperature during 1 h. At the end 50 mL (approx. 5 equiv.)of 1,3-dibromopropane was added in one lot and stirred for 42 h.Precipitated LiBr was filtered and the volatiles were removed in vacuo.The residue was partitioned between ethyl acetate (300 mL) and water(3×100 mL). The organic layer was dried (Na₂SO₄) and evaporated to givethe crude product whose purity by LC-MS analysis was 61%. Silica gelchromatography of the crude product with acetone/hexane (1:9) as eluentgave pure bromopropyl aniline (3.3 g) and an impure fraction which uponcrystallization from ethyl acetate hexane gave an additional 2.4 g. (22%yield). LC/MS: t_(R)=1.2 min; [M+H]=256, 258 (bromine pattern), ¹H NMR(CD₃OD) δ 7.07 (2H, s), 3.59 (2H, t, J_(vic)=6.4 Hz), 3.51 (2H, t,J_(vic)=8.1 Hz), 2.46 (6H, s), 2.45-2.38 (2H, m), 2.30 (3H, s).

[0522] Intermediate 33

[0523]2-Bromo-5-methyl-3-[3-(2,4,6-trimethyl-phenylamino)-propyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 7: GG)

[0524] A solution of (1.26 g, 5.4 mmol) bromoimidazole in acetone (43mL) was combined with (3-bromopropyl)-2,4,6-trimethylaniline (1.1 g,4.25 mmol) and diazabicycloundecene (1.2 equiv). After 96 h, acetone wasevaporated and the residue was partitioned between ethyl acetate (250mL) and water (3×50 mL). The organic layer was dried (Na₂SO₄) andevaporated. The residue was purified by silica gel column chromatographyusing a step gradient of 0% to 70% ethyl acetate in hexane to give 1.1 g(50% yield) of the required alkylated product. t_(R)=1.3 min., MS:[M+H]=408, 410 (bromine pattern), ¹H NMR (CDCl₃) δ 6.82 (2H, s), 4.45(2H, t, J_(vic)=7.5 Hz), 4.32 (2H, q, J_(vic)=7.1 Hz), 3.05 (2H, t,J_(vic)=7.0 Hz), 2.46 (3H, s), 2.29 (6H, s), 2.29 (3H, s), 2.05 (2H, m),1.37 (3H, t, J_(vic)7.1 Hz). ¹³CNMR (CDCl₃) δ 160.3, 148.7, 129.7,124.7, 121.1, 60.6, 46.0, 45.7, 20.6, 18.5, 16.1, 14.3. A more polarproduct (0.04 g) which corresponded to cyclization product from the N-3alkylation of imidazole was also obtained from the later fractions.

[0525] Intermediate 34

[0526]2-Bromo-5-ethyl-3-[3-(2,4,6-trimethyl-phenylamino)-propyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 7: (GG)

[0527] This compound was prepared from the corresponding2-bromoimidazole on a 12.9 mmol scale as described in the previousexample. Silica gel chromatography of the crude product using a stepgradient of 20-70% ethyl acetate in hexane provided N3-derivedcyclization product (0.47 g, 11% yield), t_(R)=1.3 min., MS: [M+H]=342,and N1-derived alkylation product (2.9 g, 54% yield); LC/MS: t_(R)=1.5min., [M+H]=422, 424 (bromine pattern), ¹H NMR (CD₃OD) δ 6.74 (2H, s),4.40 (2H, t, J_(vic)=7.6 Hz), 4.31 (2H, q, J_(vic)=7.2 Hz), 2.94 (2H, t,J_(vic)=7.1 Hz), 2.83 (2H, q, J_(vic)=7.6 Hz), 2.19 (6H, s), 2.16 (3H,s), 1.93 (2H, m), 1.34 (3H, t, J_(vic)=7.2 Hz), 1.19 (3H, t, J_(vic)=7.6Hz). ¹³CNMR (CD₃OD) δ 161.2, 154.8, 144.0, 132.7, 130.9, 130.5, 126.2,121.8, 62.0, 47.10, 46.59, 32.2, 23.70, 20.8, 18.7, 14.6, 14.5, 14.3.

[0528] Intermediate 35

[0529]2-Bromo-5-trifluoromethyl-3-[3-(2,4,6-trimethyl-phenylamino)-propyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 7: (GG)

[0530] To a 0.1M dimethylformamide solution containing 5.3 mmol each ofthe bromoimidazole and bromopropyl aniline was added 1.2 equivalents ofCs₂CO₃. The reaction mixture was stirred at ambient temperature for 96h. LC-MS indicated approximately 50% conversion to a single alkylatedproduct. Diluted with ethyl acetate (500 mL) and washed with water(3×100 mL). Approx. 5 mL ethanol had to be used to break up an emulsion.The ethyl acetate layer was dried (Na₂SO₄), evaporated in vacuo. Thecrude product was purified by silica gel chromatography with ethylacetate:hexane (1:9) as eluent. Fractions containing the requiredcompound were combined and evaporated to give 0.51 g (21% yield). LC/MS:t_(R)=1.5 min., [M+H]=462, 464 (bromine pattern), ¹H NMR (CD₃OD) δ 6.74(2H, s), 4.44 (2H, t, J_(vic)=7.5 Hz), 4.35 (2H, t, J_(vic)=7.1 Hz),2.96 (2H, t, J_(vic)=7.1 Hz), 2.20 (6H, s), 2.15 (3H, s), 1.97 (2H, m),1.33 (3H, t, J_(vic)=7.1 Hz).

[0531] Intermediate 36

[0532]2-Methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid ethyl ester, scheme 7: (HH)

[0533] The appropriate N1-alkylated 2-bromoimidazole (1 g, 2.1 mmol) insulfolane (50 mL) was heated under argon in the dark with 1.2equivalents of Ag₂CO₃ for 24h. The reaction mixture was cooled toambient temperature. Filtered, diluted with water containing 0.1%trifluoroacetic acid to 250 mL. The dark filtrate was applied to anoctadecyl silica gel (C18) column (4×15 cm) pre-equilibrated with watercontaining 0.1% trifluoroacetic acid. Elution with the same solvent wascontinued until all the sulfolane was removed. The solvent was thenchanged to methanol:0.1% trifluoroacetic acid in water (2:3) collecting25 mL size fractions which were combined after LC-MS analysis to give0.9 g of the required product as trifluoroacetate salt of 93% purity.LC/MS: t_(R)=1.1 min., [M+H] 328, ¹H NMR (CD₃OD) δ 6.94 (2H, s),4.29-4.24 (4H, m), 3.47 (2H, t, J_(vic)=5.5 Hz), 2.27 (3H, s), 2.25 (3H,s), 2.29 (3H, s), 2.24 (2H, m), 2.12 (6H, s), 1.34 (3H, t, J_(vic)=7.0Hz). ³CNMR (CD₃OD) δ 162.7, 150.3, 147.9, 139.1, 138.8, 137.8, 130.7,115.2, 60.8, 47.6, 44.4, 23.2, 21.2, 18.3, 15.2, 14.9.

[0534] Intermediate 37

[0535]2-Ethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid ethyl ester, scheme 7: (HH)

[0536] To the N1-alkylated 2-bromo-4-ethyl imidazole derivative (2.83 g,6.7 mmol) in sulfolane (67 mL) was added 1.1 equivalents of silvertriflate. The resulting solution was stirred in the dark at 150° C.under argon. Within 10 min the solution turned dark and it was stirredfor 24 h when LC-MS indicated complete conversion to cyclized product.The reaction mixture was cooled to ambient temperature. Filtered,diluted with water containing 0.1% trifluoroacetic acid to 335 mL andfiltered again. The dark filtrate was applied to an octadecyl silica gel(C18) column (4×15 cm) pre-equilibrated with water containing 0.1%trifluoroacetic acid. Elution with the same solvent was continued untilall the sulfolane was removed. The solvent was then changed tomethanol:0.1% trifluoroacetic acid in water (2:3) collecting 25 mL sizefractions which were combined after LC-MS analysis to give two majorfractions. Cyclization product that was 84% pure (1.5 g) and purecyclization product (570 mg). LC/MS: t_(R)=1.3 min., [M+H]=342,

[0537] Intermediate 38

[0538]2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrimidine-3-carboxylicacid ethyl ester, scheme 7: (HH)

[0539] The appropriate N1-alkylated-2-bromoimidazole (0.473 g, 1.02mmol) was subjected to silver triflate mediated cyclization in sulfolane(10 mL) as described above except that the reaction was carried out for48 h. At the end, the mixture was diluted with ethanol (10 mL) filteredthrough a bed (2×4.5 cm) of C18 silica gel and washed with another 50 mLmore ethanol. The filtrate was concentrated in vacuo to ca. 20 mL. Itwas then purified by preparative HPLC using a 20 min. linear gradient(25 min run) of 30-100% B in A in ten injections. Fractions containingthe cyclization product were combined and evaporated. The residue (0.39g) in 20 mL anhydrous ethanol was stirred with (0.168 g, 2 mmol) NaHCO₃for 1.5 h. Filtered and evaporated to dryness to give 0.23 g (60% yield)of cyclized product. LC/MS: t_(R)=1.8 min., [M+H] 382.

[0540] Intermediate 39

[0541][2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-yl]-methanol,scheme 7: (II)

[0542] The appropriate ethyl ester (0.032 g) in 1 mL of anhydroustetrahydrofuran was treated with an excess (0.3 mL) of 1 M LiAlH₄ intetrahydrofuran at ambient temperature. After 1 h, 1 M NaOH (5 mL) wascarefully added. Most of the tetrahydrofuran was then evaporated. Theresidue was partitioned between ethyl acetate (2×30 mL) and additional10 mL 1 M NaOH. Organic layer was dried (Na₂SO₄) and evaporated. Theresidue after silica gel chromatography with methanol:methylene chloride(1:99) yielded (0.025 g) of alcohol. LC/MS: t_(R)=1.0 min., [M+H]=340,¹H NMR (CD₃OD) δ 6.93 (2H, s), 4.62 (2H, s), 4.10 (2H, t, J_(vic)=6.1Hz), 3.51 (2H, t, J_(vic)=5.4 Hz), 2.29 (2H, m), 2.27 (3H, s), 2.13 (6H,s). Gradient NOESY experiment revealed NOE between exo methylene groupand the methylene at 6 position confirming the regiochemistry.

[0543] Intermediate 40

[0544] (3-Bromo-propyl)-(2-chloro-4,6-dimethyl-phenyl)-amine, scheme 7:FF)

[0545] To a solution of the 2-chloro-4,6-dimethyl aniline (16.9 g g, 108mmol) in 1,4-dioxane (80 mL) was added n-butyl lithium solution (2.5 Min hexanes, 48 mL), dropwise, at 0° C. under argon. The reaction mixturewas warmed up to rt and stirred for 20 min. 1,3-Dibromopropane (109 g,543 mmol) was added and the reaction mixture was stirred overnight. Themixture was filtered through celite and concentrated. Purification wascarried out by reverse phase chromatography using water, methanol andtrifluoroacetic acid to obtain product (20.01 g, 72.5 mmol, 67%) asbrown oil. LC/MS: t_(R)=1.5 min. [M+H] 277. ¹H NMR (CD₃OD) δ: 7.12 (s,1H), 6.99 (s, 1H), 3.52 (t, J=6.65 Hz, 2H), 3.36 (t, J=6.75 Hz, 2H),2.36 (s, 3H), 2.29 (s, 3H), 2.14 (m, 2H).

[0546] Intermediate 41

[0547]2-Bromo-3-[3-(2-chloro-4,6-dimethyl-phenylamino)-propyl]-5-trifluoromethyl-3H-imidazole-4-carboxylicacid ethyl ester, scheme 7: (GG)

[0548] To a solution of the imidazole (5.08 g, 17.7 mmol) in drydimethylformamide (120 mL) was added the 3-bromopropyl aniline (5.37 g,19.5 mmol) and cesium carbonate (8.64 g, 26.5 mmol) at RT under argon.The reaction mixture was heated at 55° C. overnight, cooled and dilutedwith ethyl acetate (400 mL). The organic phase was washed with water(2×), brine and dried (MgSO₄). Purification by silica gel columnchromatography using hexanes/ethyl acetate (90:10 to 70:30) affordedproduct (5.98 g, 12.4 mmol, 70%) as brown oil. LC/MS: t_(R)=2.2 min.[M+H] 483. ¹H NMR (CD₃OD) o: 6.98 (s, 1H), 6.86 (s, 1H), 4.49 (t, J=7.55Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.10 (t, J=6.95 Hz, 2H), 2.25 (s, 3H),2.19 (s, 3H), 2.00 (m, 2H), 1.34 (t, J=7.1 Hz, 3H).

[0549] Intermediate 42

[0550]1-(2-Chloro-4,6-dimethyl-phenyl)-6-trifluoromethyl-2,3,4,4a-tetrahydro-1H-[1]pyrindine-5-carboxylicacid ethyl ester, scheme 7: HH)

[0551] To a solution of the alkylated imidazole (5.98 g, 12.4 mmol) insulfolane (50 mL) was added silver triflate (4.77 g, 18.6 mmol) at rtunder argon. The flask was fitted with a reflux condenser and heated at150° C. overnight. The whole setup was covered with aluminum foil tokeep the reaction mixture in dark. The reaction mixture was filteredthrough celite and purified by reverse phase chromatography, usingwater, methanol and trifluoroacetic acid. Product (3.43 g, 8.54 mmol,69%) was obtained as brown solid. LC/MS: t_(R)=2.1 min. [M+H] 402.

[0552]¹H NMR (CD₃OD) δ: 7.01 (s, 1H), 6.92 (s, 1H), 4.38 (m, 2H), 4.32(q, J=7.15 Hz, 2H), 4.65 (m, 2H), 2.30 (m, 2H), 2.26 (s, 3H), 2.19 (s,3H), 2.00 (m, 2H), 1.33 (t, J=7.1 Hz, 3H).

[0553] Intermediate 43

[0554][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-yl]-methanol,scheme 7: (II)

[0555] To a solution of the ester (3.43 g, 8.54 mmol) in anhydroustetrahydrofuran (100 mL) at 0° C. under argon was added dropwise asolution of Lithium aluminum hydride (1 M in hexanes, 86 mL). Thereaction mixture was stirred for an hour and an aqueous solution ofRochelle salt was added dropwise to quench excess of LAH. The reactionmixture was extracted with ethyl acetate (3×100 mL). The combinedorganic layer was washed with water (2×), brine and dried (MgSO₄).Purification by silica gel column chromatography, using hexanes, ethylacetate (90:10 to 60:40) afforded product (2.12 g, 5.89 mmol, 69%) asoff white solid. LC/MS: t_(R)=1.5 min. [M+H] 360. ¹H NMR (CDCl₃) δ: 7.10(s, 1H), 6.97 (s, 1H), 4.04 (m, 2H), 3.65 (m, 2H), 3.42 (m, 2H), 2.32(m, 2H), 2.28 (s, 3H), 2.19 (s, 3H).

EXAMPLE 54

[0556]

[0557]2-Ethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 7: (LL)

[0558] A solution of 0.15 g of N-cyclopropylmethyl, N-propyl amine (1.3mmol) in toluene (5 mL) was treated with 0.47 mL of 2 Mtrimethylaluminum in hexanes (0.94 mmol). After 1 h anhydrous toluenesolution (2 mL) of the appropriate ethyl ester (59 mg, 0.17 mmol) wasadded. Refluxed for 4h. Allowed to cool to ambient temperature, dilutedwith 25 mL dichloromethane and washed with 1M NaOH (8 mL), and water (8mL). Organic layer was evaporated and the residue in 2 mLdimethylformamide was purified by prep HPLC using a 20 min lineargradient of 30-100% B in A in a 25 min run. Fractions containing therequired compound were combined to give 11 mg of the amide. LC/MS:t_(R)=1.4 min., [M+H]=409. ¹H NMR (CD₃OD) δ 7.10 (2H, s), 4.20-3.20 (8H,4×m), 2.47 (2H, m), 2.38 (2H, m), 2.33 (3H, s), 2.23 (6H, s), 1.80-1.57(2H, m), 1.22-0.20 (11H, 4×m). Fractions containing unchanged ethylester were combined to recover the starting ethyl ester (43 mg) astrifluoroacetate salt.

EXAMPLE 55

[0559]

[0560]2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrimidine-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 7: (LL)

[0561] The corresponding ethyl ester was subjected to Weinreb amidationusing standard protocols. The amide obtained was purified by PreparativeHPLC with a 15 min linear gradient of B in A in a 20 min run. Combinedfractions were evaporated in vacuo to give the required product. LC/MS:t_(R)=1.8 min., [M+H]=449, ¹H NMR (CD₃OD) δ 7.03 (2H, s), 4.04-3.97 (2H,2×m), 3.64 (2H, t, J_(vic)=5.6 Hz), 3.62-3.02 (4H, 4×m), 2.47-2.32 (2H,m), 2.31 (3H, s), 2.21 (3H, s), 2.20 (3H, s), 1.81-1.07 (3H, 3×m),1.06-0.82 (3H, 2×m), 0.70-0.02 (4H, 3×m).

[0562] Intermediate 44

[0563]2-Methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid pentafluorophenyl ester, scheme 7: (HH)

[0564] The corresponding ethyl ester (0.17 mg, 0.52 mmol) and LiOH—H₂O(110 mg) in dimethoxyethane:water (1:1, 113 mL) was heated to 55° C. for24 h. Dimethoxyethane and water were evaporated. The residue in 3 mLdimethyl formamide was treated with pentafluorophenyl trifluoroacetate(2.5 mL) and stirred for 2 h. Volatiles were evaporated and the residuewas purified by silica gel column chromatography with methylene chlorideand 2-propanol: methylene chloride (3:47). Fractions containing therequired activated pentafluorophenyl ester were combined to give 0.15 g,32% yield). LC/MS: t_(R)=1.5 min., [M+H]=466.

[0565] General Procedure for amide formation preparation of Example56-58 from Intermediate 44: The pentafluorphenyl ester (15 mg, 0.036mmol) in 1 mL dimethylformamide was stirred with 0.18 mmol ofappropriate amine and 0.18-0.36 Mmol Cs₂CO₃ at 70° C. for 18 h. Themixture was diluted with water (0.8 mL) and trifluoroacetic acid (0.2mL). The resulting solution was purified by preparative HPLC using a 20min linear gradient with 30-100% B in A as eluent in a 25 min run.Fractions containing the required product were combined and evaporatedto give the appropriate amide in 20-50% yield.

EXAMPLE 56

[0566]

[0567]2-Methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid Phenethyl-propyl-amide, scheme 7: (LL)

[0568] Prepared as described for the example above. LC/MS: t_(R)=1.3min., [M+H]=445, ¹H NMR (CD₃OD) δ 7.31-7.16 (5H, m), 7.09 (2H, s),4.31-2.72 (12H, 7×m), 2.32 (3H, s), 2.20 (6H, s), 2.05-1.43 (5H, m),1.28-0.77 (3H, 2×m).

EXAMPLE 57

[0569]

[0570]2-Methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid cyclobutylmethyl-propyl-amide, scheme 7: (LL)

[0571] LC/MS: t_(R)=1.3 min., [M+H] 409, ¹H NMR (CD₃OD) δ 7.10 (2H, s),4.43-3.79 (2H, m), 3.70 (2H, t, J_(vic)=5.5 Hz), 3.62-3.10 (4H, m),2.91-2.53 (1H, m), 2.38-2.36 (2H, m), 2.33 (3H, s), 2.22 (6H, s),2.10-1.22 (11H, 4×m), 1.16-0.79(3H, m).

EXAMPLE 58

[0572]

[0573]2-Methyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-3-carboxylicacid bis-cyclopropylmethyl-amide, scheme 7: (LL)

[0574] LC/MS: t_(R)=1.4 min., [M+H]=409, ¹H NMR (CD₃OD) δ 7.10 (2H, s),4.15-3.95 (2H, m), 3.70 (2H, t, J_(vic)=5.5 Hz), 3.68-3.36 (4H, m),2.39-2.36 (2H, m), 2.33 (3H, s), 2.23 (6H, s), 2.09 (3H, s), 1.25-1.05(4H, m), 0.41-0.05 (4H, m).

[0575] Intermediate 39 was used to prepare Examples 59-95 and 331.

EXAMPLE 59

[0576]

[0577]Cyclopropylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0578] Intermediate 39 was dissolved in benzene (50 mL) and treated withwith thionyl chloride (5 mL). The solution was heated at reflux for 2 h.The volatiles were evaporated. The residue was evaporated twice withheptane (50 mL). The resulting gum was dissolved in acetonitrile (30 mL)and treated with excess N-cyclopropylmethyl, N-propyl-amine (1 mL).After 1 h LC-MS indicated clean conversion to the requireddialkylaminomethyl derivative. Acetonitrile was evaporated and theresidue was purified by C18 column chromatography with a step gradientelution using 20-60% methanol in water containing 0.1% trifluoroaceticacid. Fractions containing the required product were combined andevaporated in vacuo to give the required amine (0.17 g, 51% overallyield from the cyclization product). LC/MS: t_(R)=1.3 min., [M+H]=435,¹H NMR (CD₃OD) δ 6.98 (2H, s), 4.56 (2H, s), 4.16 (2H, t, J_(vic)=5.8Hz), 3.60 (2H, t, J_(vic)=5.5 Hz), 3.23-3.18 (4H, 2×m), 2.36 (2H, m),2.29 (3H, s), 2.15 (6H, s), 1.81-1.76(2H, m), 1.28-1.21 (1H, m),1.02(3H, t, J_(vic)=7.3 Hz), 0.86-0.82 (2H, m), 0.51-0.47 (2H, m).

EXAMPLE 60

[0579]

[0580]3-(3,6-Dihydro-2H-pyridin-1-ylmethyl)-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0581] Prepared as described for the example above. LC/MS: t_(R)=1.3min., MS: [M+H]=405.

EXAMPLE 61

[0582]

[0583]3-Thiomorpholin-4-ylmethyl-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0584] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=425.

EXAMPLE 62

[0585]

[0586]3-Piperidin-1-ylmethyl-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0587] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=407.

EXAMPLE 63

[0588]

[0589]3-(2-Methyl-piperidin-1-ylmethyl)-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0590] Prepared as described for the example above. LC/MS: t_(R)=1.4min., MS: [M+H]=421.

EXAMPLE 64

[0591]

[0592]3-(4-Methyl-piperidin-1-ylmethyl)-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0593] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=421.

EXAMPLE 65

[0594]

[0595]Benzyl-methyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0596] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=443.

EXAMPLE 66

[0597]

[0598]Methyl-phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-Phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0599] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=457.

EXAMPLE 67

[0600]

[0601]Diallyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0602] Prepared as described for the example above. LC/MS: t_(R)=1.4min., MS: [M+H]=419.

EXAMPLE 68

[0603]

[0604]Dipropyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0605] Prepared as described for the example above. LC/MS: t_(R)=1.4min., MS: [M+H]=423.

EXAMPLE 69

[0606]

[0607]Butyl-methyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0608] Prepared as described for the example above. LC/MS: t_(R)=1.4min., MS: [M+H]=409.

EXAMPLE 70

[0609]

[0610]Butyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0611] Prepared as described for the example above. LC/MS: t_(R)=1.4min., MS: [M+H]=423.

EXAMPLE 71

[0612]

[0613]Ethyl-(2-methyl-allyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-567,8tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine, scheme 7: (KK)

[0614] Prepared as described for the example above. LC/MS: t_(R)=1.6min., MS: [M+H]=421.

EXAMPLE 72

[0615]

[0616]3-(3-Phenyl-pyrrolidin-1-ylmethyl)-2-trifluoromethyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine, scheme 7: (KK)

[0617] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=469.

EXAMPLE 73

[0618]

[0619]Cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0620] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=475.

EXAMPLE 74

[0621]

[0622]Cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-[2trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0623] Prepared as described for the example above. LC/MS: t_(R)=1.9min., MS: [M+H]=525.

EXAMPLE 75

[0624]

[0625]Cyclopropylmethyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0626] Prepared as described for the example above. LC/MS: t_(R)=1.3min., MS: [M+H]=421.

EXAMPLE 76

[0627]

[0628]Cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0629] Prepared as described for the example above. LC/MS: t_(R)=1.9min., MS: [M+H]=489.

EXAMPLE 77

[0630]

[0631]Cyclobutylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0632] Prepared as described for the example above. LC/MS: t_(R)=1.7min., MS: [M+H]=449.

EXAMPLE 78

[0633]

[0634]Propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0635] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=477.

EXAMPLE 79

[0636]

[0637]Propyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0638] Prepared as described for the example above. LC/MS: t_(R)=1.9min., MS: [M+H]=463.

EXAMPLE 80

[0639]

[0640](2,2,3,3,3-Pentafluoro-propyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0641] Prepared as described for the example above. LC/MS: t_(R)=2.0min., MS: [M+H]=513.

EXAMPLE 81

[0642]

[0643]Phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0644] Prepared as described for the example above. LC/MS: t_(R)=2.0min., MS: [M+H]=539.

EXAMPLE 82

[0645]

[0646]Phenethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0647] Prepared as described for the example above. LC/MS: t_(R)=1.9min., MS: [M+H]=525.

EXAMPLE 83

[0648]

[0649]Phenethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0650] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=485.

EXAMPLE 84

[0651]

[0652]Ethyl-phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0653] Prepared as described for the example above. LC/MS: t_(R)=1.7min., MS: [M+H]=471.

EXAMPLE 85

[0654]

[0655]Benzyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0656] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=511.

EXAMPLE 86

[0657]

[0658]Benzyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0659] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=525.

EXAMPLE 87

[0660]

[0661](2-Cyclopropyl-ethyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0662] Prepared as described for the example above. LC/MS: t_(R)=1.7min., MS: [M+H]=449.

EXAMPLE 88

[0663]

[0664](2-Cyclopropyl-ethyl)-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0665] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=435.

EXAMPLE 89

[0666]

[0667](2-Cyclopropyl-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0668] Prepared as described for the example above. LC/MS: t_(R)=2.0min., MS: [M+H]=503.

EXAMPLE 90

[0669]

[0670](2-Cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0671] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=489.

EXAMPLE 91

[0672]

[0673](4-Fluoro-benzyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0674] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=543.

EXAMPLE 92

[0675]

[0676](4-Fluoro-benzyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0677] Prepared as described for the example above. LC/MS: t_(R)=1.7min., MS: [M+H]=489.

EXAMPLE 93

[0678]

[0679](4-Chloro-benzyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0680] Prepared as described for the example above. LC/MS: t_(R)=1.9min., MS: [M+H]=559.

EXAMPLE 94

[0681]

[0682](4-Chloro-benzyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0683] Prepared as described for the example above. LC/MS: t_(R)=1.8min., MS: [M+H]=505.

EXAMPLE 95

[0684]

[0685]Allyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0686] Prepared as described for the example above. LC/MS: t_(R)=1.5min., MS: [M+H]=421.

[0687] Intermediate 43 was used to prepare Examples 96-138.

EXAMPLE 96

[0688]

[0689][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclopropylmethyl-propyl-amine,scheme 7: (KK)

[0690] To a solution of the appropriate alcohol (0.092 mg, 0.25 mmol) inbenzene (20 mL) was added thionyl chloride (0.15 g, 1.28 mmol) at 0° C.,under argon. The reaction mixture was stirred for an hour the solventwas removed on a rotary evaporator. Traces of thionyl chloride wereremoved by co-evaporating with dichloromethane 3 times. The residue wasdissolved in dichloromethane (50 mL) and to that solution was added theN-propyl-cyclopropylmethylamine (0.058 g, 0.512 mmol) anddiisopropylethyl amine (0.099 g, 0.768 mmol) at rt. The reaction mixturewas stirred overnight. Solvent was concentrated, the residue dissolvedin methanol (2 mL) and purification carried out by reverse phasepreparative HPLC using water, methanol, trifluoroacetic acid to obtainthe product (0.084 g, 0.15 mmol, 70%) as colorless oil. LC/MS: t_(R)=1.4min. [M+H] 455. ¹H NMR (CD₃OD) δ: 7.20 (s, 1H), 7.11 (s, 1H), 4.58 (m,2H), 4.19 (m, 2H), 3.68 (m, 1H), 3.59 (m, 1H), 3.23 (m, 4H), 2.39 (m,2H), 2.33 (s, 3H), 2.23 (s, 3H), 1.79 (m, 2H), 1.22 (m, 1H), 1.01 (t,J=7.3 Hz, 3H0, 0.83 (m, 2H), 0.50 (m, 2H).

EXAMPLE 97

[0691]

[0692]8-(2-Chloro-4,6-dimethyl-phenyl)-3-morpholin-4-ylmethyl-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0693] Prepared as described for the example above. LC/MS: t_(R)=1.3min. [M+H] 429.

EXAMPLE 98

[0694]

[0695]8-(2-Chloro-4,6-dimethyl-phenyl)-3-thiomorpholin-4-ylmethyl-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0696] Prepared as described for the example above. LC/MS: t_(R)=1.3min. [M+H) 445.

EXAMPLE 99

[0697]

[0698]8-(2-Chloro-4,6-dimethyl-phenyl)-3-piperidin-1-ylmethyl-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0699] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 427.

EXAMPLE 100

[0700]

[0701]8-(2-Chloro-4,6-dimethyl-phenyl)-3-(2-methyl-piperidin-1-ylmethyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0702] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 101

[0703]

[0704]8-(2-Chloro-4,6-dimethyl-phenyl)-3-(3-methyl-piperidin-1-ylmethyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0705] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 102

[0706]

[0707]8-(2-Chloro-4,6-dimethyl-phenyl)-3-(4-methyl-piperidin-1-ylmethyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0708] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 103

[0709]

[0710]Diallyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0711] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 439.

EXAMPLE 104

[0712]

[0713]Butyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-methyl-amine,scheme 7: (KK)

[0714] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 429.

EXAMPLE 105

[0715]

[0716]Benzyl-butyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-amine,scheme 7: (KK)

[0717] Prepared as described for the example above. LC/MS: t_(R)=1.6min. [M+H] 506.

EXAMPLE 106

[0718]

[0719][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-ethyl-(2-methyl-allyl)-amine,scheme 7: (KK)

[0720] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 107

[0721]

[0722]Benzyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-methyl-amine,scheme 7: (KK)

[0723] Prepared as described for the example above. LC/MS: t_(R)=1.5min. [M+H] 463.

EXAMPLE 108

[0724]

[0725]Butyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-ethyl-amine,scheme 7: (KK)

[0726] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 443.

EXAMPLE 109

[0727]

[0728][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-dipropyl-amine,scheme 7: (KK)

[0729] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 443.

EXAMPLE 110

[0730]

[0731][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2-methoxy-ethyl)-propyl-amine,scheme 7: (KK)

[0732] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 459.

EXAMPLE 111

[0733]

[0734][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclobutylmethyl-propyl-amine,scheme 7: (KK)

[0735] Prepared as described for the example above. LC/MS: t_(R)=1.5min. [M+H] 470.

EXAMPLE 112

[0736]

[0737][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 7: (KK)

[0738] Prepared as described for the example above. LC/MS: t_(R)=1.9min. [M+H] 509.

EXAMPLE 113

[0739]

[0740][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclopropylmethyl-ethyl-amine,scheme 7: (KK)

[0741] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 114

[0742]

[0743][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-propyl-(2,2,2-trifluoro-ethyl)-amine,scheme 7: (KK)

[0744] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 483.

EXAMPLE 115

[0745]

[0746][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amine,scheme 7: (KK)

[0747] Prepared as described for the example above. LC/MS: t_(R)=1.9min. [M+H] 545.

EXAMPLE 116

[0748]

[0749][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-propyl-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0750] Prepared as described for the example above. LC/MS: t_(R)=1.7min. [M+H] 497.

EXAMPLE 117

[0751]

[0752][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2,2,3,3,3-pentafluoro-propyl)-propyl-amine,scheme 7: (KK)

[0753] Prepared as described for the example above. LC/MS: t_(R)=1.9min. [M+H] 533.

EXAMPLE 118

[0754]

[0755][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-phenethyl-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0756] Prepared as described for the example above. LC/MS: t_(R)=1.9min. [M+H] 560.

EXAMPLE 119

[0757]

[0758][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-phenethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 7: (KK)

[0759] Prepared as described for the example above. LC/MS: t_(R)=1.9min. [M+H] 545.

EXAMPLE 120

[0760]

[0761][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-ethyl-phenethyl-amine,scheme 7: (KK)

[0762] Prepared as described for the example above. LC/MS: t_(R)=1.6min. [M+H] 491.

EXAMPLE 121

[0763]

[0764][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-phenethyl-propyl-amine,scheme 7: (KK)

[0765] Prepared as described for the example above. LC/MS: t_(R)=1.6min. [M+H] 505.

EXAMPLE 122

[0766]

[0767][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2-cyclopropyl-ethyl)-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0768] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 523.

EXAMPLE 123

[0769]

[0770][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2-cyclopropyl-ethyl)-ethyl-amine,scheme 7: (KK)

[0771] Prepared as described for the example above. LC/MS: t_(R)=1.5min. [M+H] 455.

EXAMPLE 124

[0772]

[0773][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2-cyclopropyl-ethyl)-propyl-amine,scheme 7: (KK)

[0774] Prepared as described for the example above. LC/MS: t_(R)=1.5min. [M+H] 469.

EXAMPLE 125

[0775]

[0776]Benzyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0777] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 545.

EXAMPLE 126

[0778]

[0779][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(2-cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-amine,scheme 7: (KK)

[0780] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 509.

EXAMPLE 127

[0781]

[0782][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(4-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0783] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 563.

EXAMPLE 128

[0784]

[0785](4-Chloro-benzyl)-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0786] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 580.

EXAMPLE 129

[0787]

[0788](4-Chloro-benzyl)-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-propyl-amine,scheme 7: (KK)

[0789] Prepared as described for the example above. LC/MS: t_(R)=1.7min. [M+H] 526.

EXAMPLE 130

[0790]

[0791]Benzyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-propyl-amine,scheme 7: (KK)

[0792] Prepared as described for the example above. LC/MS: t_(R)=1.5min. [M+H] 491.

EXAMPLE 131

[0793]

[0794]Allyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-propyl-amine,scheme 7: (KK)

[0795] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 441.

EXAMPLE 132

[0796]

[0797][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(4-fluoro-benzyl)-propyl-amine,scheme 7: (KK)

[0798] Prepared as described for the example above. LC/MS: t_(R)=1.6min. [M+H] 509.

EXAMPLE 133

[0799]

[0800][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine,scheme 7: (KK)

[0801] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 563.

EXAMPLE 134

[0802]

[0803][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(3-fluoro-benzyl)-propyl-amine,scheme 7: (KK)

[0804] Prepared as described for the example above. LC/MS: t_(R)=1.6min. [M+H] 509.

EXAMPLE 135

[0805]

[0806][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclopropylmethyl-(2,2,2-trifluoroethyl)-amine,scheme 7: (KK)

[0807] Prepared as described for the example above. LC/MS: t_(R)=1.8min. [M+H] 495.

EXAMPLE 136

[0808]

[0809][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-(4-nitro-benzyl)-propyl-amine,scheme 7: (KK)

[0810] Prepared as described for the example above. LC/MS: t_(R)=1.7min. [M+H] 536.

EXAMPLE 137

[0811]

[0812][8-(2-Chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-3-ylmethyl]-cyclobutylmethyl-ethyl-amine,scheme 7: (KK)

[0813] Prepared as described for the example above. LC/MS: t_(R)=1.4min. [M+H] 455.

EXAMPLE 138

[0814]

[0815]3-(2-Benzyl-pyrrolidin-1-ylmethyl)-8-(2-chloro-4,6-dimethyl-phenyl)-2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[0816] LC/MS: t_(R)=1.5 min. [M+H] 503.

[0817] The following Intermediates 45-94 may be used to synthesizeExamples 139-282.

[0818] Intermediate 45

[0819] (4-Fluoro-2-nitro-phenyl)-(2,4,6-trimethyl-phenyl)-amine¹, scheme1: (B)

[0820] A mixture of 2,4,6-trimethlaniline (42.1 mL, 300 mmol),2,5-difluoro-nitrobenzene (16.3 mL, 150 mmol) and anhydrous potassiumfluoride (10.5 g, 180 mmol) was heated and stirred at 180° C. for 60 h.After cooling, the mixture was partitioned between dichloromethane (170mL) and water (150 mL). The aqueous layer was extracted withdichloromethane (60 mL). The combined organic layers were washed withwater and brine. Solvents were removed in vacuo and the residue purifiedby silica gel chromatography eluting with 40% dichloromethane/hexanes toafford the title compound as a red solid (36.92 g, 100% yield). ¹H NMR(CDCl₃, 300 MHz) δ 9.00 (s, 1H), 7.93 (dd, J=9.1, 3.0 Hz, 1H), 7.12-7.05(m, 1H), 6.99 (s, 2H), 6.37 (dd, J=9.4, 4.7 Hz, 1H), 2.33 (s, 3H), 2.14(s, 6H); ³C NMR (CDCl₃, 75 MHz) δ 154.6, 151.4, 141.8, 137.6, 136.3,132.6, 129.6, 124.9 (d, J=23.8 Hz), 116.5 (d, J=7.0 Hz), 111.75 (d,J=26.2 Hz).

[0821] Intermediate 46

[0822] (2-Nitro-phenyl)-(2,4,6-trimethyl-phenyl)-amine:³, scheme 1: (B)

[0823] Prepared as described for the example above. Chromatography usingdichloromethane/hexanes (30%) as eluent and recrystallization fromanhydrous ethanol afforded the title compound as orange needle crystals(15.4 g, 40% yield).

[0824]¹H NMR (CDCl₃, 300 MHz) δ 9.13 (br s, 1H), 8.23 (d, J=8.4 Hz, 1H),7.28 (t, J=7.2 Hz, 1H), 7.00 (s, 2H), 6.70 (t, J=7.2 Hz, 1H), 6.39 (d,J=8.4 Hz, 1H), 2.35 (s, 3H), 2.16 (s, 6H).

[0825] Intermediate 47

[0826] (2-Bromo-4-isopropyl-phenyl)-(2-nitro-phenyl)-amine, scheme 1:(B)

[0827] Prepared as described for the example above. Chromatography usingdichloromethane/hexanes (20%) as eluent and vacuum distillation toremove unreacted 2-bromo-4-iso-propylaniline afforded the title compoundas a red solid (12 g, 24% yield). ¹H NMR (CDCl₃, 300 MHz) δ 9.41 (br s,1H), 8.21 (dd, J=8.6, 1.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.38-7.33 (m,2H), 7.20 (dd, J=8.1, 2.0 Hz, 1H), 7.08 (dd, J=8.6, 1.0 Hz, 1H), 6.81(t, J=7.0 Hz, 1H), 2.92 (septet, J=7.0 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H).

[0828] Intermediate 48

[0829] (2,4-Dichloro-phenyl)-(2-nitro-phenyl)-amine, scheme 1: (B)

[0830] Prepared as described for the example above. Chromatography usingdichloromethane/hexanes (10% and 20%) as eluent and recrystallizationfrom 95% ethanol afforded the title compound as red needle crystals (8.5g, 20% yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.39 (s, 1H), 8.22 (dd, J=8.5,1.5 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.45-7.38 (m, 2H), 7.27 (dd, J=8.6,2.3 Hz, 1H), 7.13 (dd, J=8.6, 1.0 Hz, 1H), 6.88 (td, J=7.8, 1.2 Hz, 1H);¹³C NMR (CDCl₃, 100 MHz) δ 141.0, 135.7, 135.1, 134.6, 130.5, 130.3,129.3, 127.9, 126.8, 124.8, 118.9, 116.2.

[0831] Intermediate 49

[0832] (3-Nitro-pyridin-2-yl)-(2,4,6-trimethyl-phenyl)-amine, scheme 1:(B)

[0833] A mixture of 2-chloro-3-nitro-pyridine (24.05 g, 152 mmol),2,4,6-trimethylaniline (60 ml, 427 mmol), and Cs₂CO₃ (59.4 g, 182.4mmol) was heated at 100° C. for 24 h. Flash chromatography using 1)methylene chloride/Hexanes (1:4) and 2) methylene chloride, followed byrecrystallization from 95% ethanol. The title compound was obtained asan orange-yellow crystals (17.0 g, 44% yield). ¹H NMR (CDCl₃, 5 MHz) δ9.38 (s, 1H), 8.51 (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 7.00 (s, 2H), 6.73(s, 1H), 2.34 (s, 3H), 2.18(s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 156.2,152.1, 137.2, 135.7, 135.4, 132.3, 129.1, 128.3, 112.8, 21.1, 18.5.

[0834] Intermediate 50

[0835] (2-Chloro-4,6-dimethylphenyl)-(3-nitro-pyridin-2-yl)-amine,scheme 1: (B)

[0836] A mixture of 2-chloro-3-nitro-pyridine (55.8 g, 352 mmol),2-chloro-4,6-trimethylaniline (110 g, 704 mmol), and KF (28.6 g, 493mmol) was heated at 190° C. for 40 h. After cooling to room temperature,the mixture was extracted with methylene chloride and 1N NaOH. Thecombined organic layers were washed with water and brine, then driedover MgSO₄. Solvents were removed in vacuo, and the residue wassubjected to vacuum distillation to remove unreacted2-chloro-4,6-trimethylaniline. The resulting brownish solid wassubjected to flash chromatography using 1) methylene chloride/hexanes(1:1) and 2) methylene chloride, followed by recrystallization from 95%ethanol. The title compound was obtained as yellow crystals (9.8 g, 10%yield). ¹H NMR (CDCl₃, 500 MHz) δ 9.39 (br s, 1H), 8.51 (dd, J=8.3, 1.8Hz, 1H), 8.37 (dd, J=4.5, 1.7 Hz, 1H), 7.18 (s, 1H), 7.04 (s, 1H), 6.78(dd, J=8.3, 4.5 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H).

[0837] Intermediate 51

[0838] 4-Fluoro-N]-(2,4,6-trimethyl-phenyl)-benzene-1,2-diamine, scheme1: (C) Palladium on carbon (10%) (0.54 g) was added to a solution of(4-fluoro-2-nitro-phenyl)-(2,4,6-trimethyl-phenyl)-amine (5.32 g, 19.4mmol) in ethyl acetate (40 mL) under nitrogen at room temperature in a500 mL round-bottomed flask. The flask was evacuated under high vacuum(<2 mm Hg) and purged with hydrogen six times at room temperature, thenit was attached to a balloon filled with hydrogen. After the reactionmixture was stirred at room temperature for 4.0 h under 1 atmosphere ofhydrogen, the balloon was removed and a stream of nitrogen was bubbledthrough the reaction mixture for 10 min. The reaction mixture wasfiltered through a pad of celite and solvents were removed in vacuo toafford the title compound as a red solid (4.74 g, 100% yield). Thepurity of this compound was determined to be 98% by LC/MS. ¹H NMR(CDCl₃, 300 MHz) δ 6.93 (s, 2H), 6.52 (dd, J=9.8, 2.7 Hz, 1H), 6.32 (td,J=8.6, 2.7 HZ, 1H), 6.22 (dd, J=8.7, 5.7 Hz, 1H), 2.32 (s, 3H), 2.12 (s,6H); ¹³C NMR (CDCl₃, 75 MHz) δ 159.8, 156.7, 138.2 (d, J=10.5 Hz),137.6, 133.5, 132.3, 129.5, 117.3 (d, J=9.5 Hz), 105.1 (d, J=22 Hz),102.9 (d, J=25.5 Hz),20.8, 18.0; Mass spec.: 245.14 (MH⁺)

[0839] Intermediate 52

[0840] N-(2,4,6-Trimethyl-phenyl)-benzene-1,2-diamine, scheme 1: (C)

[0841] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 6.92 (s, 2H), 6.88 (d, J=7.5 Hz, 1H), 6.78-6.70 (m, 2H), 6.25 (d,J=7.2 Hz, 1H), 4.95 (br s, 2H), 2.31 (s, 3H), 2.13 (s, 6H); Mass spec.:227.15 (MH⁺)

[0842] Intermediate 53

[0843] N-(2,4-Dichloro-phenyl)-benzene-1,2-diamine, scheme 1: (C)

[0844] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.31-7.00 (m, 4H), 6.89-6.79 (m, 2H), 6.52 (d, J=8.8 Hz, 1H),5.74 (s, 1H), 4.27 (br s, 2H); Mass spec.: 253.12 (MH⁺)

[0845] Intermediate 54

[0846] N²-(2,4,6-Trimethyl-phenyl)-pyridine-2,3-diamine, scheme 1: (C)

[0847] Prepared as described for the example above. Mass spec.: 228.16(MH⁺)

[0848] Intermediate 55

[0849] N-(2-Bromo-4-isopropyl-phenyl)-benzene-1,2-diamine², scheme 1:(C)

[0850] To a solution of(2-bromo-4-isopropyl-phenyl)-(2-nitro-phenyl)-amine (8.2 g, 24.5 mmol)in tetrahydrofuran (35 mL) and water (35 mL) at room temperature, wasadded NH₄OH (33.6 mL) and Na₂S₂O₄ (21.3 g, 122.5 mmol. After stirring atroom temperature for 5 h, water (70 mL) was added and the mixture wasextracted with ethyl acetate (175 mL). After separation, the aqueouslayer was saturated with NaCl, and extracted with ethyl acetate (3×60mL). The combined organic layers were washed with sat. NaHCO₃, water,brine, and dried over Na₂SO₄. Solvents were removed in vacuo to affordthe title compound a red viscous liquid (5.3 g, 71% yeld). The purity ofthis compound was determined to be 95% by LC/MS and it was used for thenext step without further purification. Mass spec.: 307.08 (MH⁺).

[0851] Intermediate 56

[0852] N²-(2-Chloro-4,6-dimethyl-phenyl)-pyridine-2,3-diamine, scheme 1:(C)

[0853] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.71 (dd, J=5.0, 1.5 Hz, 1H), 7.11 (s, 1H), 6.97 (dd, J=7.5, 1.6Hz, 1H), 6.96 (s, 1H), 6.67 (dd, J=7.5, 5.0 Hz, 1H), 5.89 (br s, 1H),3.53 (br s, 2H), 2.29 (s, 3H), 2.13 (s, 3H); Mass spec.: 228.16 (MH⁺)

[0854] Intermediate 57

[0855] 5-Fluoro-1-(2,4,6-trimethyl-phenyl)-1H-benzoimidazol-2-ylamine:³,scheme 1: (D)

[0856] A solution of cyanogen bromide (2.67 g, 25.2 mmol) in anhydrousethanol (10 mL) was added at 0° C. to a solution of4-fluoro-N¹-(2,4,6-trimethyl-phenyl)-benzene-1,2-diamine (4.74 g, 19.4mmol) in anhydrous ethanol (20 mL) under nitrogen. The reaction mixturewas warmed up to room temperature for 10 min, then was heated at 155° C.for 40 min with a flow of nitrogen to remove ethanol. Upon cooling toroom temperature, the resulting solids were transferred to a separatoryfunnel via dichloromethane (70 mL), and washed sequentially with 1 Nsodium hydroxide (2×35 mL), water and brine. The organic layer was driedover anhydrous sodium sulfate and solvents were removed in vacuo toafford the title compound as a red solid (5.11 g, 98% yield). The purityof this compound was determined to be 95% by LC/MS. ¹H NMR (CDCl₃, 300MHz) δ 7.12 (dd, J=9.7, 2.4 Hz, 1H), 7.06 (s, 2H), 6.69 (td, J=9.1, 2.4Hz, 1H), 6.56 (dd, J=8.5, 4.7 Hz, 1H), 2.38 (s, 3H), 1.98 (s, 6H); ¹³CNMR (CDCl₃, 75 MHz) δ 161.0, 157.9, 154.2, 143.3, 139.9, 137.4, 129.8,128.8, 107.8 (d, J=10.2 Hz), 106.9 (d, J=25.3 Hz), 103.1 (d, J=25.2Hz)21.1, 17.5; Mass spec.: 270.17 (MH⁺).

[0857] Intermediate 58

[0858] 1-(2,4,6-Trimethyl-phenyl)-1H-benzoimidazol-2-ylamine, scheme 1:(D)

[0859] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.46 (d, J=8.1 Hz, 1H), 7.16 (td, J=7.6, 1.2 Hz, 1H), 7.06 (s,2H), 7.01 (td, J=7.2, 0.6 Hz, 1H), 6.71 (dd, J=7.8, 0.6 Hz, 1H), 2.38(s, 3H), 1.98 (s, 6H); Mass spec.: 252.09 (MH⁺)

[0860] Intermediate 59

[0861] 1-(2,4-Dichloro-phenyl)-1H-benzoimidazol-2-ylamine, scheme 1: (D)

[0862] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.67 (d, J=1.5 Hz, 1H), 7.49-7.41 (m, 2H), 7.23-7.16 (m, 2H),7.04 (t, J=7.7 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H); Mass spec.: 278.08 (MH⁺)

[0863] Intermediate 60

[0864] 1-(2-Bromo-4-isopropyl-phenyl)-1H-benzoimidazol-2-ylamine, scheme1: (D)

[0865] Prepared as described for the example above. Mass spec.: 330.08(MH⁺)

[0866] Intermediate 61

[0867] 3-(2,4,6-Trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-ylamine,scheme 1: (D)

[0868] To a mixture of N 2-(2,4,6-Trimethyl-phenyl)-pyridine-2,3-diamine(3.05 g, 13.4 mmol), NaHCO₃ (2.03 g, 24.1 mmol) in ethanol (40 mL) at 0°C., was added a solution of BrCN (2.55 g, 24.1 mmol) in ethanol (6 mL).The resulting mixture was stirred at 0° C. for 1 h, room temperature for8 h, and then 80° C. for 8 h. Ethanol was removed in vacuo and theresidue was taken up into a separatory funnel with methylene chloride(100 mL). The mixture was washed sequentially with 1N NaOH, water andbrine, then the organic layer was dried over Na₂SO₄. After removingsolvents, a brown solid was obtained. By LC-MS, the solid was a mixtureof the desired product and the unreacted starting material in a ratio of4:1 in favor of the desired product. Mass spec.: 253.17 (MH⁺).

[0869] Intermediate 62

[0870]3-(2-Chloro-4,6-dimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-ylamine,scheme 1: (D)

[0871] Prepared as described for the example above. Mass spec.273.20(MH⁺)

[0872] Intermediate 63

[0873]3-Ethoxycarbonylmethyl-1-(2,4,6-trimethylphenyl)-2-amino-5-fluoro-benimidazoliumbromide:⁴, scheme 1: (E)

[0874] Ethyl bromoacetate (2.3 mL, 20.9 mmol) was added at roomtemperature to a solution of5-fluoro-1-(2,4,6-trimethyl-phenyl)-1H-benzoimidazol-2-ylamine (5.11 g,19.0 mmol) in acetone (100 mL). The resulting mixture was heated atreflux for 14 h. Upon cooling to room temperature, acetone was removedin vacuo. Solids were transferred onto a filtering funnel and washedwith ether (2×1 5 mL) to afford the title compound as a pink solid (7.42g, 90%). The solids were used for the next step without furtherpurification. ¹H NMR (CDCl₃, 300 MHz) δ 8.44 (s, 2H), 7.11 (s, 2H),7.11-6.96 (m, 2H), 6.78 (dd, J=8.6, 4.1 Hz, 1H), 5.69 (s, 2H), 4.28 (qd,J=7.1, 1.0 Hz, 2H), 2.38 (s, 3H), 2.02 (s, 6H), 1.32 (td, J=7.1, 1.2 Hz,3H); ³C NMR (CDCl₃, 75 MHz) δ 165.8, 162.0, 158.7, 151.1, 142.3, 136.9,130.7, 126.2, 124.7, 112.4 (d, J=25.0 Hz), 111.2 (d, J=9.4 Hz), 98.7 (d,J=29.2 Hz), 63.0, 46.8, 21.3, 17.4, 14.1.

[0875] Intermediate 64

[0876]3-Ethoxycarbonylmethyl-1-(2,4,6-trimethylphenyl)-2-aminobenimidazoliumbromide, scheme 1: (E)

[0877] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.21 (s, 2H), 7.37 (dd, J=7.5, 1.2 Hz, 1H), 7.32-7.28 (m, 2H),7.12 (s, 2H), 6.86 (d, J=7.8 Hz, 1H), 5.71 (s, 2H), 4.29 (q, J=7.2 Hz,2H), 2.40 (s, 3H), 2.03 (s, 6H), 1.33 (t, J=7.5 Hz, 3H).

[0878] Intermediate 65

[0879]3-Ethoxycarbonylmethyl-1-(2,4-dichlorolphenyl)-2-aminobenimidazoliumbromide, scheme 1: (E)

[0880] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 9.16 (s, 2H), 7.68 (d, J=1.9 Hz, 1H), 7.60-7.55 (m, 2H),7.34-7.19 (m, 3H), 6.83 (d, J=7.8 Hz, 1H), 5.55 (s, 2H), 4.26 (q, J=7.6Hz, 2H), 1.30 (t, J=7.8 Hz, 3H).

[0881] Intermediate 66

[0882]2-Amino-3-(2-bromo-4-isopropyl-phenyl)-1-ethoxycarbonylmethyl-3H-benzoimidazol-1-iumbromide, scheme 1: (E)

[0883] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.48 (s, 2H), 7.72 (s, 1H), 7.47 (s, 2H), 7.39-7.24 (m, 3H), 6.91(d, J=7.8 Hz, 1H), 5.66 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.03 (sept.,J=6.9 Hz, 1H), 1.32 (d, J=6.9 Hz, 6H), 1.30 (t, J=7.1 Hz, 3H).

[0884] Intermediate 67

[0885]2-Amino-1-ethoxycarbonylmethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-1-iumbromide, scheme 1: (E)

[0886] Prepared as described for the example above. Mass spec.: 339.21(M-HBr+H)⁺.

[0887] Intermediate 68

[0888]2-Amino-3-(2-chloro-4,6-dimethyl-phenyl)-1-ethoxycarbonylmethyl-3H-imidazo[4,5-b]pyridin-1-iumbromide, scheme 1: (E)

[0889] Prepared as described for the example above. Mass spec.: 359.20(M−HBr+H)⁺.

[0890] Intermediate 69

[0891]5-Fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester:⁴, scheme 1: (F)

[0892] A mixture of3-ethoxycarbonylmethyl-1-(2,4,6-trimethylphenyl)-2-amino-5-fluoro-benimidazoliumbromide (2.0 g, 4.59 mmol), sodium acetate (0.94 g, 11.4 mmol) andacetic anhydride (14.0 mL) was heated at 160° C. for 20 h. Upon cooling,the mixture was poured into a flask containing ice. While stirring,excess sodium bicarbonate was added to the above mixture in smallportions, and the resulting mixture was stirred at room temperature for6 h. Then, the mixture was extracted with dichloromethane (2×70 mL). Theorganic extracts were washed with water and dried over anhydrous sodiumsulfate. Solvents were removed in vacuo and the residue was subjected tochromatography using ethyl acetate/hexanes (1:9) as eluent to afford thetitle compound as a white solid (1.33 g, 76% yield). ¹H NMR (CDCl₃, 300MHz) δ 8.39 (d, J=9.3 Hz, 1H), 7.03 (s, 2H), 6.98 (dd, J=9.0, 2.2 Hz,1H), 6.81 (dd, J=8.8, 4.5 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.63 (s, 3H),2.35 (s, 3H), 1.95 (s, 6H), 1.48 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 75MHz) δ 161.1, 159.6, 156.4, 153.1, 149.3, 139.7, 136.9, 129.9 (d, J=228Hz), 129.7, 125.8 (d, J=13.6 Hz), 112.9, 111.1 (d, J=25.0 Hz), 110.4 (d,J=9.5 Hz), 103.2 (d, J=30 Hz), 60.3, 21.1, 17.7, 16.6, 14.7; Mass spec.:380.21 (MH⁺).

[0893] Intermediate 70

[0894]2-Ethyl-5-fluoro-8-(2,4,6-trimethyl-phenyl)-8H-1.3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0895] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.38 (dd, J=9.4, 2.4 Hz, 1H), 7.03 (s, 2H), 7.01-6.95 (m, 1H),6.80 (dd, J=8.8, 4.5 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.01 (q, J=7.6 Hz,2H), 2.35 (s, 3H), 1.95 (s, 6H), 1.47 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.6Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 161.0, 159.6, 159.0, 156.4, 149.7,139.7, 136.9, 130.0 (d, J=227 Hz), 129.8, 125.7 (d, J=14.0 Hz), 112.8,111.1 (d, J=24.9 Hz), 110.4 (d, J=9.6 Hz), 103.3 (d, J=29.6 Hz), 60.3,23.7, 21.1, 17.7, 14.6, 14.4; Mass spec.: 394.19 (MH⁺)

[0896] Intermediate 71

[0897]2-Methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0898] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.43-8.40 (m, 1H), 7.12-7.06 (m, 2H), 6.85 (s, 2H), 6.73-6.70 (m,1H), 4.29 (q, J=7.2 Hz, 2H), 2.46 (s, 3H), 2.17 (s, 3H), 1.77 (s, 6H),1.29 (t, J=7.2 Hz, 3H); ³C NMR (CDCl₃, 75 MHz) δ 161.1, 152.6, 148.4,139.5, 136.9, 135.0, 129.6, 128.5, 125.8, 123.7, 121.3115.3, 113.0,110.1, 60.1, 21.1, 17.6, 16.6, 14.6; Mass spec.: 362.10 (MH⁺)

[0899] Intermediate 72

[0900]2-Ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0901] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.61-8.58 (m, 1H), 7.30-7.23 (m, 2H), 7.03 (s, 2H), 6.91-6.88 (m,1H), 4.48 (q, J=7.1 Hz, 3H), 3.03 (q, J=7.5 Hz, 2H), 2.36 (s, 3H), 1.96(s, 6H), 1.48 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.4 Hz); Mass spec.: 376.23(MH⁺)

[0902] Intermediate 73

[0903]2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0904] Prepared as described for the example above but in a sealed bomb(170° C., 60 h).

[0905]¹H NMR (CDCl₃, 300 MHz) δ 8.76-8.73 (m, 1H), 7.43-7.34 (m, 2H),7.08 (s, 2H), 7.01-6.98 (m, 1H), 4.54 (q, J=7.12 Hz, 2H), 2.39 (s, 3H),1.99 (s, 6H), 1.50 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 159.1,147.0, 139.9, 139.1 (q, J=39.0 Hz), 136.9, 135.7, 129.7, 128.0, 125.4,125.0, 121.9, 120.9 (q, J=268 Hz), 116.4, 110.6, 61.4, 21.0, 17.6, 14.0;Mass spec.: 416.09 (MH⁺)

[0906] Intermediate 74

[0907]8-(2,4-Dichloro-phenyl)-2-methyl-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0908] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.59-8.56 (m, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.5 Hz,1H), 7.44 (dd, J=8.4, 2.1 Hz, 1H), 7.31-7.24 (m, 2H), 7.02-6.99 (m, 1H),4.44 (q, J=7.0 Hz, 2H), 2.62 (s, 3H), 1.45 (t, J=7.1 Hz, 3H); ¹³C NMR(CDCl₃, 75 MHz) δ 161.0, 152.3, 148.4, 136.2, 135.0, 133.9, 131.1,131.0, 130.5, 128.8, 126.1, 123.9, 122.1, 115.5, 113.5, 110.6, 60.3,16.6, 14.6; Mass spec.: 388.10 (MH⁺).

[0909] Intermediate 75

[0910]8-(2,4-Dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0911] Prepared as described for the example above but in a sealed bomb(170° C., 60 h).

[0912]¹H NMR (CDCl₃, 500 MHz) δ 8.69 (d, J=8.2 Hz, 1H), 7.68 (d, J=2.2Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.5, 2.2 Hz, 1H), 7.43-7.37(m, 2H), 7.09 (d, J=8.2 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2Hz, 3H); Mass spec.: 442.05 (MH⁺).

[0913] Intermediate 76

[0914]8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0915] Prepared as described for the example above but in a sealed bomb(170° C., 60 h). Mass spec.: 494.10 (MH⁺).

[0916] Intermediate 77

[0917]2-Methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0918] Prepared as described for the example. ¹H NMR (CDCl₃, 500 MHz) δ8.77 (dd, J=8.1, 1.2 Hz, 1H), 8.29 (dd, J=4.9, 1.2 Hz, 1H), 7.23 (dd,J=8.1, 5.0 Hz, 1H), 7.04 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 2.65 (s, 3H),2.34 (s, 3H), 1.98 (s, 6H), 1.49 (t, J=7.1 Hz, 3H). Mass spec.: 363.22(MH⁺).

[0919] Intermediate 78

[0920]2-Ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0921] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.78 (dd, J=8.1, 1.4 Hz, 1H), 8.28 (dd, J=5.0, 1.4 Hz, 1H), 7.23(dd, J=8.1, 5.0 Hz, 1H), 7.04 (s, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.01 (q,J=7.5 HZ, 2H), 2.34 (s, 3H), 1.98 (s, 6H), 1.47 (t, J=7.1 Hz, 3H), 1.28(t, J=7.5 Hz, 3H). Mass spec.: 377.20 (MH⁺).

[0922] Intermediate 79

[0923]2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0924] Prepared as described for the example above but in a sealed bomb(170° C., 60 h).

[0925]¹H NMR (CDCl₃, 500 MHz) δ 8.93 (dd, J=8.1, 1.4 Hz, 1H), 8.41 (dd,J=4.9, 1.4 Hz, 1H), 7.32 (dd, J=8.1, 4.9 HZ, 1H), 7.06 (s, 2H), 4.51 (q,J=7.1 Hz, 2H), 2.36 (s, 3H), 1.98 (s, 6H), 1.47 (t, J=7.1 Hz, 3H). Massspec.: 417.20 (MH⁺).

[0926] Intermediate 80

[0927]8-(2-Chloro-4,6-dimethylphenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester, scheme 1: (F)

[0928] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.78 (dd, J=8.1, 1.4 Hz, 1H), 8.29 (dd, J=5.0, 1.5 Hz, 1H), 7.26(s, 1H), 7.25 (dd, J=8.1, 5.0 Hz, 1H), 7.14 (s, 1H), 4.48 (q, J=7.2 Hz,2H), 2.65 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.48 (t, J=7.2 Hz, 3H).Mass spec.: 383.16 (MH⁺).

[0929] Intermediate 81

[0930][2-Trifluoromethyl-8-(2,4,6-trimethylphenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-yl]-methanol,scheme 2: (I)

[0931] To a solution oftrifluoromethyl-trimethylphenyl-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester (2.51 g, 6.05 mmol) in tetrahydrofuran (40 mL) wasadded LiAlH₄ (1.0 M solution in ether, 18.2 mL, 18.2 mmol) at 0° C. Theresulting clear solution was stirred at 0° C. for 1 h and then quenchedat 0° C. by the sequential additions of water (0.69 mL), 15% aq.NaOH(0.69 mL) and water (2.1 mL). The mixture was warmed up to roomtemperature and filtered through a pad of celite®. After removingsolvents in vacuo, the title compound was obtained as an off-white solid(2.26 g, 100% yield), which was pure by LC-MS and ¹H NMR. ¹H NMR (CDCl₃,500 MHz) δ 7.97 (dd, J=7.2, 1.8 Hz, 1H), 7.32-7.29 (m, 2H), 7.03 (s,2H), 6.92 (dd, J=7.2, 2.0 Hz, 1H), 5.14 (s, 2H), 2.35 (s, 3H), 1.98 (s,6H); Mass spec: 374.23 (MH⁺).

[0932] Intermediate 82

[0933][8-(2,4-Dichlorophenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[a]inden-3-yl]-methanol,scheme 2: (I)

[0934] To a solution of8-(2,4-Dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylicacid ethyl ester (490 mg, 1.11 mmol) in methylene chloride (20 mL), wasadded at 0° C. a toluene solution of DIBAL-H (5.55 mL, 5.55 mmol). Afterstirring at 0° C. for 75 min, the reaction mixture was cooled down to−78° C. and methanol (2.2 mL) was added dropwise, followed by additionsof ground Na₂SO₄-10H₂O (15.2 g) and celite (2.6 mL). The resultingmixture was warmed up to room temperature in 4 h. After filtration, thesolvents were removed in vacuo to afford the title compound as an offwhite solid (443 mg, 100% yield). ¹H NMR (CDCl₃, 500 MHz) δ 8.00-7.93(m, 1H), 7.65 (d, J=2.2 Hz, 1H0, 7.57 (d, J=7.4 Hz, 1H), 7.46 (dd,J=8.6, 2.3 Hz, 1H), 7.37-7.33 (m, 2H), 7.08-7.05 (m, 1H); Mass spec.:400.02 (MH⁺).

[0935] Intermediate 83

[0936][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-yl]-methanol,scheme 2: (I)

[0937] Prepared as the example shown above (DIBAL-H reduction) in 100%yield and used for the next step without further purification. ¹H NMR(CDCl₃, 300 MHz) δ 7.96 (d, J=8.9 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.46(d, J=8.1 Hz, 1H), 7.36-7.31 (m, 2H), 7.17 (d, J=7.3 Hz, 1H), 7.08 (d,J=9.0 Hz, 1H), 5.12 (s, 2H), 2.97 (sept., J=6.9 Hz, 1H), 2.36 (s, 1H),1.30 (d, J=6.9 Hz, 6H); Mass spec.: 454.07 (MH⁺).

[0938] Intermediate 84

[0939][2-Methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol,scheme 2: (I)

[0940] Prepared as the example shown above (DIBAL-H reduction). Massspec.: 321.20 (MH⁺)

[0941] Intermediate 85

[0942][2-Ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol,scheme 2: (1)

[0943] Prepared as the example shown above (DIBAL-H reduction). ¹H NMR(CDCl₃, 300 MHz) δ 8.22 (dd, J=5.1, 1.4 Hz, 1H), 8.04 (dd, J=7.9 Hz,1H), 7.16 (dd, J=7.9, 5.1 Hz, 1H), 7.03 (s, 2H), 4.95 (d, J=4.6 Hz, 2H),2.68 (q, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.02 (s, 6H), 1.25 (t, J=7.5 Hz,3H); Mass spec.: 335.25 (MH⁺).

[0944] Intermediate 86

[0945][2-Trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol,scheme 2: (I)

[0946] Prepared as the example shown above (DIBAL-H reduction). ¹H NMR(CDCl₃, 500 MHz) δ 8.34 (dd, J=5.0, 1.4 Hz, 1H), 8.23 (dd, J=8.0, 1.4Hz, 1H), 7.24 (dd, J=8.0, 5.0 Hz, 1H), 7.04 (s, 2H), 5.11 (s, 2H), 2.33(s, 3H), 2.01 (s, 6H); Mass spec.: 375.20 (MH⁺).

[0947] Intermediate 87

[0948][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-113a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol,scheme 2: (I)

[0949] Prepared as the example shown above (DIBAL-H reduction). ¹H NMR(CDCl₃, 300 MHz) δ 8.23 (dd, J=5.1, 1.3 Hz, 1H), 8.04n (dd, J=7.9, 1.4Hz, 1H), 7.24 (s, 1H), 7.17 (dd, J=7.9, 5.1 Hz, 1H), 7.11 (s, 1H), 4.93(s, 2H), 2.36)s, 3H), 2.31 (s, 3H), 2.14 (s, 3H); Mass spec.: 341.15(MH⁺).

[0950] Intermediate 88

[0951]3-Chloromethyl-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene:⁵,scheme 2: (J)

[0952] A sealed tube containing(trifluoromethyl-trimethylphenyl-8H-1,3a,8-triaza-cyclopenta[a]inden-3-yl)-methanol(1.1 g, 2.95 mmol) and SOCl₂ (3.5 mL) was heated at 80° C. for 1 h.After removing SOCl₂ in vacuo, the title compound was obtained as alight brown viscous liquid (1.15 g, 100% yield), which was pure by

[0953]¹H NMR. ¹H NMR (CDCl₃, 500 MHz) d 7.94-7.92 (m, 1H), 7.39-7.37 (m,2H), 7.05 (s, 2H), 7.00-6.98 (m, 1H), 5.18 (s, 2H), 2.37 (s, 3H), 1.99(s, 6H); Mass spec. 388.30 [M−Cl+OMe+H]⁺.

[0954] Intermediate 89

[0955]3-Chloromethyl-8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene,scheme 2: (J)

[0956] Prepared as the example shown above (SOCl₂ neat, 80° C., 30 min).Mass spec. 414.08 [M−Cl+OMe+H]⁺.

[0957] Intermediate 90

[0958]8-(2-Bromo-4-isopropyl-phenyl)-3-chloromethyl-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene,scheme 2: (J)

[0959] Prepared as the example shown above (SOCl₂ neat, 80° C., 30 min).Mass spec. 466.10 [M−Cl+OMe+H]⁺.

[0960] Intermediate 91

[0961]3-Chloromethyl-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene:⁶,scheme 2: (J)

[0962] Thionyl chloride. (0.164 mL, 2.25 mmol) was added at 0° C. to asolution of[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-yl]-methanol(0.36 g, 1.12 mmol) in CH₂Cl₂ (10 mL). After 2 h, solvents was removedand the title compound was obtained as a brownish oil (100% yield). Massspec.: 335.24 (M−Cl+OMe+H)⁺.

[0963] Intermediate 92

[0964]3-Chloromethyl-2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (J)

[0965] Prepared as the example shown above (SOCl₂, CH₂Cl₂, 0° C., 2 h).Mass spec.: 349.22 (M−Cl+OMe+H)⁺.

[0966] Intermediate 93

[0967]3-Chloromethyl-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (J)

[0968] Prepared as the example shown above (SOCl₂, CH₂Cl₂, 0° C., 2 h).Mass spec.: 389.20 (M−Cl+OMe+H)⁺.

[0969] Intermediate 94

[0970]8-(2-Chloro-4,6-dimethyl-phenyl)-3-chloromethyl-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (J)

[0971] Prepared as the example shown above (SOCl₂, CH₂Cl₂, 0° C., 2 h).Mass spec.: 355.16(M−Cl+OMe+H)⁺.

[0972] For Examples 139-141 and 143-149, LC/MS were run using thefollowing conditions: Column, YMC ODS S7 3.0×50 mm; run time, 3 mins.For Example 142, the LC/MS was run using the following conditions:Column, YMC C18 S5 4.6×50 mm; run time, 4 mins.

EXAMPLE 139

[0973]

[0974]5-Fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide:⁷, scheme 1: (G)

[0975] A solution of trimethylaluminum (2.0 M in heptane, 1.4 mL, 2.8mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.40mL, 2.8 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up toroom temperature and stirred at this temperature for 1.5 hours, and thenadded to a stirred solution of5-fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid ethyl ester (0.13 g, 0.35 mmol) in benzene (2.0 mL). The mixturewas refluxed for 12 hours. Upon cooling at 0° C., 1 N sodium hydroxide(15 mL) was added dropwise to the above mixture. The mixture wasextracted with dicholoromethane (30 mL), and the organic layer was driedover anhydrous sodium sulfate. Solvents were removed in vacuo and theresidue was subjected to chromatography using ethyl acetate/hexanes(3:7) as eluent to afford the title compound as an off-white solid(0.156 g, 100% yield).

[0976]¹H NMR (CDCl₃, 300 MHz) δ 7.60 (dd, J=8.7, 2.5 Hz, 1H), 6.99 (s,2H), 6.92 (td, J=9.0, 2.5 Hz, H), 6.75 (dd, J=8.8, 4.4 Hz, H), 3.66 (t,J=7.1 Hz, 2H), 3.46 (d, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 1.92(s, 6H), 1.71-1.63 (m, 2H), 1.11-1.05 (m, 1H), 0.88 (t, J=7.2 Hz, 3H),0.57-0.53 (m, 2H), 0.19-0.16 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 163.6,159.4, 156.3, 148.9, 143.3, 139.4, 137.0, 131.6, 129.7, 128.7, 124.8 (d,J=13 Hz), 114.2, 110.6 (d, J=25 Hz), 101.2 (d, J=29 Hz), 51.3, 48.6,21.1, 21.0, 17.8, 15.7, 11.3, 10.1, 3.8. LC/MS: t_(R)=1.95 min, 447.22(MH⁺).

EXAMPLE 140

[0977]

[0978]2-Methyl-8-(2,4,6-trimethyl-phenyl)-8H-1.3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 1: (G)

[0979] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.86-7.82 (m, 1H), 7.23-7.19 (m, 2H), 7.02 (s, 2H), 6.89-6.86 (m,1H), 3.69 (t, J=7.0 Hz, 2H), 3.49 (d, J=6.9 Hz, 2H), 2.39 (s, 3H), 2.35(s, 3H), 1.98 (s, 6H), 1.74-1.65 (m, 2H), 1.16-1.06 (m, 1H), 0.90 (t,J=7.2 Hz, 3H), 0.59-0.53 (m, 2H), 0.23-0.20 (m, 2H); ¹³C NMR (CDCl₃, 75MHz) δ 163.7, 147.9, 139.2, 137.0, 135.2, 129.5, 128.8, 124.8, 123.3,121.0, 114.2, 113.1, 110.2, 60.3, 51.1, 21.0, 17.7, 15.4, 11.2, 10.1,3.8; LC/MS: t_(R)=1.95 min, 429.13 (MH⁺).

EXAMPLE 141

[0980]

[0981]2-Ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 1: (G)

[0982] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.81-7.76 (m, 1H), 7.23-7.16 (m, 2H), 7.02 (s, 2H), 6.87-6.84 (m,1H), 3.68 (t, J=6.6 Hz, 2H), 3.49 (d, J=6.7 Hz, 2H), 2.70 (q, J=7.4 Hz,2H), 2.35 (s, 3H), 1.98 (s, 6H), 1.73-1.63 (m, 2H), 1.28 (t, J=7.4 Hz,3H), 1.15-1.05 (m, 1H), 0.89 (t, J=7.3 Hz, 3H), 0.57-0.54 (m, 2H),0.25-0.20 (m, 2H); LC/MS: t_(R)=1.95 min, 443.23 (MH⁺).

EXAMPLE 142

[0983]

[0984]2-trifluoromethyl-8-(2,4,6-trimethylphenyl)-8H-1.3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 1: (G)

[0985] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.72-7.66 (m, 1H), 7.32-7.20 (m, 2H), 7.02 (s, 2H), 6.91 (d,J=7.8 Hz, 1H), 3.80-3.26 (m, 4H), 2.33 (s, 3H), 1.97 (s, 6H), 1.82-1.53(m, 2H), 1.33-1.20 (m, 1H), 1.04 (t, J=7.2 Hz, 3H), 0.95-0.83 (m, 2H),0.74-0.59 (m, 2H); LC/MS: t_(R)=2.86 min, 483.30 (MH⁺).

EXAMPLE 143

[0986]

[0987]8-(2,4-Dichloro-phenyl)-2-methyl-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 1: (G)

[0988] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.82-7.79 (m, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.53 (d, J=8.5 Hz,1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.25-7.22 (m, 2H), 7.02-6.99 (m, 1H),3.68 (t, J=7.0 Hz, 2H), 3.48 (d, J=6.8 Hz, 2H), 2.38 (s, 3H), 1.75-1.63(m, 2H), 1.13-1.07 (m, 1H), 0.90 (t, J=7.8 Hz, 3H), 0.59-0.53 (m,2H)0.22-0.19 (m, 2H); LC/MS: t_(R)=1.88 min, 455.11 (MH⁺).

EXAMPLE 144

[0989]

[0990]2-Ethyl-5-fluoro-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 1: (G)

[0991] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.58 (dd, J=8.6, 2.5 Hz, 1H), 7.02 (s, 2H), 6.95 (t, J=9.6 Hz,1H), 6.79-6.76 (m, 1H), 3.68 (t, J=6.9 Hz, 2H), 3.49 (d, J=6.8 Hz, 2H),2.70 (q, J=7.3 Hz, 2H), 2.35 (s, 3H), 1.98 (s, 6H), 1.73-1.63 (m, 2H),1.28 (t, J=7.4 Hz, 3H), 1.15-1.10 (m, 1H), 0.92 (t, J=7.3 Hz, 3H),0.59-0.54 (m 2H), 0.22-0.19 (m, 2H);

[0992]¹³C NMR (CDCl₃, 75 MHz) δ 163.7, 159.4, 156.2, 148.9, 139.4,137.0, 131.6, 129.7, 128.8, 124.7 (d, J=9.0 Hz), 113.0, 110.5 (d, J=11.4Hz), 110.3, 101.0, 51.4, 48.7, 22.8, 21.1, 17.8, 13.8, 11.3, 10.1, 3.8;LC/MS: t_(R)=2.05 min, 461.26 (MH⁺).

EXAMPLE 145

[0993]

[0994]Cyclopropylmethyl-[5-fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine:8, scheme 1: (H)

[0995] A solution of Red-Al (3.3 M in toluene, 0.25 mL, 0.8 mmol) wasadded dropwise to a solution of2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylicacid cyclopropylmethyl-propyl-amide (73 mg, 0.16 mmol) in toluene (2 mL)at 0° C. After stirring at room temperature for 24 hours, the reactionmixture was cooled to 0° C. and 1 N sodium hydroxide (10 mL) was addeddropwise. The above mixture was extracted with dichloromethane (30 mL),and the organic extracts were washed with water and dried over anhydroussodium sulfate. Solvents were removed in vacuuo and the residue wassubjected to chromatography using ethyl acetate/hexanes as eluent toafford the title compound as a white solid (59.4 mg, 86% yield). ¹H NMR(CDCl₃, 300 MHz) δ 7.87 (dd, J=9.1, 2.2 Hz, 1H), 7.00 (s, 2H), 6.88 (td,J=−9.0, 2.5 Hz, 1H), 6.70 (dd, J=8.8, 4.5 Hz, 1H), 3.89 (s, 2H), 2.52(t, J=7.3 Hz, 2H), 2.46 (d, J=6.6 Hz, 2H), 2.34 (s, 3H), 2.29 (s, 3H),1.97 (s, 6H), 1.49-1.42 (m, 2H), 1.05-1.00 (m, 1H), 0.74 (t, J=7.3 Hz,3H), 0.56-0.51 (m, 2H), 0.16-0.14 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ159.3, 156.2, 148.3, 139.0, 138.8, 137.2, 130.5 (d, J=179.5 Hz), 129.6,125.4 (d, J=13.0 Hz)115.8, 109.6, 109.3 (d, J=25.8 Hz), 101.3 (d, J=29.2Hz), 59.0, 55.3, 48.8, 21.1, 19.7, 17.7, 13.8, 12.0, 8.7, 4.3; LC/MS:t_(R)=1.57 min, 433.22 (MH⁺).

EXAMPLE 146

[0996]

[0997]Cyclopropylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 1: (H)

[0998] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.05-7.99 (m, 1H), 7.18-7.12 (m, 2H), 6.94 (s, 2H), 6.80-6.74 (m,1H), 3.96 (s, 2H), 2.52 (t, J=6.8 Hz, 2H), 2.44 (d, J=6.9 Hz, 2H), 2.36(s, 3H), 2.30 (s, 3H), 1.98 (s, 6H), 1.50-1.44 (m, 2H), 1.05-0.98 (m,1H), 0.77 (t, J=7.2 Hz, 3H), 0.55-0.50 (m, 2H), 0.16-0.12 (m 2H); LC/MS:t_(R)=1.39 min, 415.23 (MH⁺).

EXAMPLE 147

[0999]

[1000]Cyclopropylmethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine,scheme 1: (H)

[1001] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 8.05-8.01 (m, 1H), 7.19-7.12 (m, 2H), 7.11 (s, 2H), 6.82-6.79 (m,1H), 3.93 (s, 2H), 2.65 (q, J=7.5 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.48(d, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.98 (s, 6H), 1.49-1.42 (m, 2H), 1.23(t, J=7.5 Hz, 3H), 1.08-0.98 (m, 1H), 0.74 (t, J=7.3 Hz, 3H), 0.53-0.49(m, 2H), 0.13-0.10 (m, 2H); LC/MS: t_(R)=1.71 min, 429.25 (MH⁺).

EXAMPLE 148

[1002]

[1003]Cyclopropylmethyl-propyl-(trifluoromethyl-trimethylphenyl-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl)-amine,scheme 1: (H)

[1004] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.37-7.33 (m, 1H), 7.27-7.24 (m, 1H), 7.16 (d, J=7.4 Hz, 1H),7.04 (s, 2H), 6.97-6.94 (m, 1H), 4.95 (s, 2H), 3.27-3.16 (m, 4H), 2.22(s, 3H), 1.96 (s, 6H), 1.87-1.79 (m, 2H), 1.23-1.20 (m, 1H), 0.97 (t,J=7.2 Hz, 3H), 0.84-0.80 (m, 2H), 0.46-0.43 (m, 2H); LC/MS: t_(R)=1.57min, 469.31 (MH⁺).

EXAMPLE 149

[1005]

[1006]Cyclopropylmethyl-[2-ethyl-5-fluoro-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-propyl-amine,scheme 1: (H)

[1007] Prepared as described for the example above. ¹H NMR (CDCl₃, 300MHz) δ 7.89 (dd, J=9.1, 2.5 Hz, 1H), 7.00 (s, 2H), 6.87 (td, J=9.1, 2.6Hz, 1H), 6.69 (dd, J=8.8, 4.5 Hz, 1H), 3.90 (s, 2H), 2.63 (q, J=7.5 Hz,2H), 2.53 (t, J=7.3 Hz, 2H), 2.47 (d, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.97(s, 6H), 1.48-1.41 (m, 2H), 1.23 (t, J=7.5 Hz, 3H), 1.05-0.95 (m, 1H),0.74 (t, J=7.3 Hz, 3H), 0.56-0.52 (m, 2H), 0.15-0.12 (m, 2H); ¹³C NMR(CDCl₃, 75 MHz) δ 159.3, 156.1, 148.4, 145.1, 139.0, 137.2, 130.6 (d,J=174 Hz), 129.6, 125.5 (d, J=13.3 Hz), 115.0, 109.6, 109.2 (d, J=24.8Hz), 101.4 (d, J=29.2 Hz), 59.1, 55.4, 48.8, 21.4, 21.1, 19.8, 17.8,15.2, 12.0, 8.8, 4.3; LC/MS: t_(R)=1.78 min, 447.27 (MH⁺).

[1008] General Procedure for the Synthesis of Examples 150-282:

[1009] (For Examples 150-252 LC/MS were run using the followingconditions: Column, YMC S5 4.6×50 mm; run time, 4 mins.)

[1010] An amine hydrochloride salt or a free amine (0.65 mmol, 5 equiv.)was added to an oven-dried 11 mL vial. After the addition of anhydrousacetonitrile (1 mL) and anhydrous i-Pr₂NEt (0.16 mL, 0.91 mmol, 7 equivin the case of an amine-HCl salt, or 43 μL, 0.26 mmol, 2 equiv in thecase of a free amine), the mixture was stirred at room temperature for 1h, followed by the addition of a solution of a chloromethyl compound(0.13 mmol) in MeCN (1 mL). The resulting mixture was stirred at roomtemperature for 24 h, or heated at 80° C. for 16 h if atrifluoromethyl-containing amine hydrochloride salt was employed. Afterremoving solvents and excess of i-Pr₂NEt in vacuo, the residue wasdissolved in dimethylformamide or acetonitrile (2 mL) and CF₃CO₂H (30μL) was added. The mixture (in most cases, a clear solution) wasfiltered into a Prep-HPLC vial, and title compounds were obtained byPrep-HPLC.

EXAMPLE 150

[1011]

[1012]Cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethylphenyl-8H-1,3a,8-triaza-cyclopenta[a]inden-3-ylmethyl]-amine,scheme 2: (H)

[1013] Prepared as described for the example above. LC/MS: t_(R)=2.99min, 509.23 (MH⁺).

EXAMPLE 151

[1014]

[1015]Bis-cyclopropylmethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1016] Prepared as described for the example above. LC/MS: t_(R)=2.15min, 481.28 (MH⁺).

EXAMPLE 152

[1017]

[1018]Cyclopropylmethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1019] Prepared as described for the example above. LC/MS: t_(R)=2.86min, 523.24 (MH⁺).

EXAMPLE 148

[1020]

[1021]Cyclopropylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1022] Prepared as described for the example above. LC/MS: t_(R)=1.57min, 469.26 (MH⁺).

EXAMPLE 153

[1023]

[1024]Cyclobutylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1025] Prepared as described for the example above. LC/MS: t_(R)=2.28min, 483.29 (MH⁺).

EXAMPLE 154

[1026]

[1027]Cyclopropylmethyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1028] Prepared as described for the example above. LC/MS: t_(R)=2.06min, 455.24 (MH⁺).

EXAMPLE 155

[1029]

[1030]Cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1031] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 559.22 (MH⁺).

EXAMPLE 156

[1032]

[1033]Cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1034] Prepared as described for the example above. LC/MS: t_(R)=3.08min, 523.23 (MH⁺).

EXAMPLE 157

[1035]

[1036]Propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1037] Prepared as described for the example above. LC/MS: t_(R)=2.87min, 511.23 (MH⁺).

EXAMPLE 158

[1038]

[1039](2,2,3,3,3-Pentafluoro-propyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1040] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 547.22 (MH⁺).

EXAMPLE 159

[1041]

[1042]Propyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1043] Prepared as described for the example above. LC/MS: t_(R)=2.98min, 497.23 (MH⁺).

EXAMPLE 160

[1044]

[1045]Diallyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1046] Prepared as described for the example above. LC/MS: t_(R)=2.26min, 453.27.

EXAMPLE 161

[1047]

[1048]Phenethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1049] Prepared as described for the example above. LC/MS: t_(R)=2.42min, 519.44 (MH⁺).

EXAMPLE 162

[1050]

[1051](2,2,3,3,3-Pentafluoro-propyl)-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1.3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1052] Prepared as described for the example above. LC/MS: t_(R)=2.87min, 551.18 (MH⁺).

EXAMPLE 163

[1053]

[1054]Ethyl-phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1055] Prepared as described for the example above. LC/MS: t_(R)=2.31min, 505.43 (MH⁺).

EXAMPLE 164

[1056]

[1057](2-Cyclopropyl-ethyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1058] Prepared as described for the example above. LC/MS: t_(R)=2.25min, 483.30 (MH⁺).

EXAMPLE 165

[1059]

[1060]Benzyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2:

[1061] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 559.24 (MH⁺).

EXAMPLE 166

[1062]

[1063](2-Cyclopropyl-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1064] Prepared as described for the example above. LC/MS: t_(R)=2.99min, 537.25 (MH⁺).

EXAMPLE 167

[1065]

[1066]Benzyl-methyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1067] Prepared as described for the example above. LC/MS: t_(R)=2.24min, 477.25 (MH⁺).

EXAMPLE 168

[1068]

[1069]Phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1070] Prepared as described for the example above. LC/MS: t_(R)=3.10min, 585.12 (MH⁺).

EXAMPLE 169

[1071]

[1072](2-Cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1073] Prepared as described for the example above. LC/MS: t_(R)=3.04min, 523.24 (MH⁺).

EXAMPLE 170

[1074]

[1075]Butyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1076] Prepared as described for the example above. LC/MS: t_(R)=2.14min, 457.26 (MH⁺).

EXAMPLE 171

[1077]

[1078]Phenethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-Phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1079] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 559.24 (MH⁺).

EXAMPLE 172

[1080]

[1081](2-Cyclopropyl-ethyl)-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1082] Prepared as described for the example above. LC/MS: t_(R)=2.17min, 469.29 (MH⁺);

EXAMPLE 173

[1083]

[1084]Benzyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1085] Prepared as described for the example above. LC/MS: t_(R)=2.70min, 491.26 (MH⁺).

EXAMPLE 174

[1086]

[1087]Ethyl-phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1088] Prepared as described for the example above. LC/MS: t_(R)=3.02min, 505.43 (MH⁺).

EXAMPLE 175

[1089]

[1090]Benzyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1091] Prepared as described for the example above. LC/MS: t_(R)=2.46min, 505.26 (MH⁺).

EXAMPLE 176

[1092]

[1093]Benzyl-butyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1094] Prepared as described for the example above. LC/MS: t_(R)=2.57min, 519.27 (MH⁺).

EXAMPLE 177

[1095]

[1096]Bis-cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1097] Prepared as described for the example shown above. LC/MS:t_(R)=2.08 min, 507.15 (MH⁺).

EXAMPLE 178

[1098]

[1099]Cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1100] Prepared as described for the example above. LC/MS: t_(R)=2.07min, 495.17 (MH⁺).

EXAMPLE 179

[1101]

[1102]Cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1103] Prepared as described for the example above. LC/MS: t_(R)=2.92min, 535.09 (MH⁺).

EXAMPLE 180

[1104]

[1105]Cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine, scheme 2: (H)

[1106] Prepared as described for the example above. LC/MS: t_(R)=2.76min, 549.11 (MH⁺).

EXAMPLE 181

[1107]

[1108]Cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-ethyl-amine,scheme 2: (H)

[1109] Prepared as described for the example above. LC/MS: t_(R)=1.98min, 481.13 (MH⁺).

EXAMPLE 182

[1110]

[1111][8-(2,4-Dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-propyl-amine,scheme 2: (H)

[1112] Prepared as described for the example above. LC/MS: t_(R)=2.39min, 545.17 (MH⁺).

EXAMPLE 183

[1113]

[1114]Cyclopropylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2,2,3,3,3-pentafluoro-propyl)-amine,scheme 2: (H)

[1115] Prepared as described for the example above. LC/MS: t_(R)=2.99min, 585.09 (MH⁺).

EXAMPLE 184

[1116]

[1117]Diallyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1118] Prepared as described for the example above. LC/MS: t_(R)=2.17min, 479.14 (MH⁺).

EXAMPLE 185

[1119]

[1120]Cyclobutylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1121] Prepared as described for the example above. LC/MS: t_(R)=3.00min, 549.12 (MH⁺).

EXAMPLE 186

[1122]

[1123]Cyclobutylmethyl-[8-(2,4-dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1124] Prepared as described for the example above. LC/MS: t_(R)=2.18min, 509.16 (MH⁺).

EXAMPLE 187

[1125]

[1126][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-bis-cyclopropylmethyl-amine,scheme 2: (H)

[1127] Prepared as described for the example shown above. LC/MS:t_(R)=2.29 min, 559.28 (MH⁺).

EXAMPLE 188

[1128]

[1129][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1130] Prepared as described for the example above. LC/MS: t_(R)=3.04min, 589.22 (MH⁺).

EXAMPLE 189

[1131]

[1132][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1133] Prepared as described for the example above. LC/MS: t_(R)=2.87min, 603.24 (MH⁺).

EXAMPLE 190

[1134]

[1135][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-ethyl-amine,scheme 2: (H)

[1136] Prepared as described for the example above. LC/MS: t_(R)=2.32min, 535.26 (MH⁺).

EXAMPLE 191

[1137]

[1138][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amine,scheme 2: (H)

[1139] Prepared as described for the example above. LC/MS: t_(R)=3.07min, 639.22 (MH⁺).

EXAMPLE 192

[1140]

[1141]Diallyl-[8-(2-bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1142] Prepared as described for the example above. LC/MS: t_(R)=2.39min, 533.24 (MH⁺).

EXAMPLE 193

[1143]

[1144][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-propyl-amine,scheme 2: (H)

[1145] Prepared as described for the example above. LC/MS: t_(R)=2.53min, 599.30 (MH⁺).

EXAMPLE 194

[1146]

[1147][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1148] Prepared as described for the example above. LC/MS: t_(R)=3.09min, 603.25 (MH⁺).

EXAMPLE 195

[1149]

[1150][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-propyl-amine,scheme 2: (H)

[1151] Prepared as described for the example above. LC/MS: t_(R)=2.38min, 563.29 (MH⁺).

EXAMPLE 196

[1152]

[1153][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-ethyl-phenethyl-amine,scheme 2: (H)

[1154] Prepared as described for the example above. LC/MS: t_(R)=2.42min, 585.27 (MH⁺).

EXAMPLE 197

[1155]

[1156][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1157] Prepared as described for the example above. LC/MS: t_(R)=2.88min, 591.24 (MH⁺).

EXAMPLE 198

[1158]

[1159]Allyl-[8-(2-bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1160] Prepared as described for the example above. LC/MS: t_(R)=2.29min, 535.26 (MH⁺).

EXAMPLE 199

[1161]

[1162][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(4-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1163] Prepared as described for the example above. LC/MS: t_(R)=3.05min, 657.22 (MH⁺).

EXAMPLE 200

[1164]

[1165][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (M)

[1166] Prepared as described for the example above. LC/MS: t_(R)=3.00min, 577.23 (MH⁺).

EXAMPLE 201

[1167]

[1168][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1169] Prepared as described for the example above. LC/MS: t_(R)=3.08min, 639.24 (MH⁺).

EXAMPLE 202

[1170]

[1171]Benzyl-[8-(2-bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1172] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 639.23 (MH⁺).

EXAMPLE 203

[1173]

[1174][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-butyl-ethyl-amine,scheme 2: (H)

[1175] Prepared as described for the example above. LC/MS: t_(R)=2.27min, 537.27 (MH⁺).

EXAMPLE 204

[1176]

[1177][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2-cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-amine,scheme 2: (H)

[1178] Prepared as described for the example above. LC/MS: t_(R)=3.07min, 603.24 (MH⁺).

EXAMPLE 205

[1179]

[1180][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2,2,3,3,3-pentafluoro-propyl)-propyl-amine,scheme 2: (H)

[1181] Prepared as described for the example above. LC/MS: t_(R)=3.06min, 627.22 (MH⁺).

EXAMPLE 206

[1182]

[1183][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-dipropyl-amine,scheme 2: (H)

[1184] Prepared as described for the example above. LC/MS: t_(R)=2.36min, 537.20 (MH⁺).

EXAMPLE 207

[1185]

[1186][8-(2-Bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-(2-cyclopropyl-ethyl)-ethyl-amine,scheme 2: (H)

[1187] Prepared as described for the example above. LC/MS: t_(R)=3.52min, 549.29 (MH⁺).

EXAMPLE 208

[1188]

[1189]Benzyl-[8-(2-bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-ethyl-amine,scheme 2: (H)

[1190] Prepared as described for the example above. LC/MS: t_(R)=2.43min, 571.26 (MH⁺).

EXAMPLE 209

[1191]

[1192]Benzyl-[8-(2-bromo-4-isopropyl-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1193] Prepared as described for the example above. LC/MS: t_(R)=2.47min, 585.27 (MH⁺).

EXAMPLE 210

[1194]

[1195]Cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1196] Prepared as described for the example above. LC/MS: t_(R)=2.86min, 510.23 (MH⁺).

EXAMPLE 211

[1197]

[1198]Cyclopropylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1199] Prepared as described for the example above. LC/MS: t_(R)=2.00min, 470.26 (MH⁺).

EXAMPLE 212

[1200]

[1201]Cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cylopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1202] Prepared as described for the example above. LC/MS: t_(R)=2.94min, 560.21 (MH⁺).

EXAMPLE 213

[1203]

[1204]Cyclopropylmethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1205] Prepared as described for the example above. LC/MS: t_(R)=2.79min, 524.24 (MH⁺).

EXAMPLE 214

[1206]

[1207]Bis-cyclopropylmethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1208] Prepared as described for the example above. LC/MS: t_(R)=2.01min, 482.27 (MH⁺).

EXAMPLE 215

[1209]

[1210]Cyclobutylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1211] Prepared as described for the example above. LC/MS: t_(R)=2.18min, 484.28 (MH⁺).

EXAMPLE 216

[1212]

[1213]Cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1214] Prepared as described for the example above. LC/MS: t_(R)=2.96min, 524.24 (MH⁺).

EXAMPLE 217

[1215]

[1216]Phenethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1217] Prepared as described for the example above. LC/MS: t_(R)=2.45min, 520.27 (MH⁺).

EXAMPLE 218

[1218]

[1219]Ethyl-phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1220] Prepared as described for the example above. LC/MS: t_(R)=2.27min, 506.26 (MH⁺).

EXAMPLE 219

[1221]

[1222]Diallyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1223] Prepared as described for the example above. LC/MS: t_(R)=2.15min, 454.24 (MH⁺).

EXAMPLE 220

[1224]

[1225]Allyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1226] Prepared as described for the example above. LC/MS: t_(R)=2.03min, 456.25 (MH⁺).

EXAMPLE 221

[1227]

[1228] (4)Propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1229] Prepared as described for the example above. LC/MS: t_(R)=2.79min, Mass spec.: 512.24 (MH⁺).

EXAMPLE 222

[1230]

[1231]Propyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1232] Prepared as described for the example above. LC/MS: t_(R)=2.84min, 498.22 (MH⁺).

EXAMPLE 223

[1233]

[1234]Cyclopropylmethyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[alinden-3-ylmethyl]-amine, scheme 2: (H)

[1235] Prepared as described for the example above. LC/MS: t_(R)=1.90min, 456.25 (MH⁺).

EXAMPLE 224

[1236]

[1237](2,2,3,3,3-Pentafluoro-propyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1238] Prepared as described for the example above. LC/MS: t_(R)=2.94min, 548.21 (MH⁺).

EXAMPLE 225

[1239]

[1240](2-Cyclopropyl-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1241] Prepared as described for the example above. LC/MS: t_(R)=2.93min, 538.26 (MH⁺).

EXAMPLE 226

[1242]

[1243]Phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-aminescheme-2:(H)

[1244] Prepared as described for the example above. LC/MS: t_(R)=2.99min, 574.25 (MH⁺).

EXAMPLE 227

[1245]

[1246]Benzyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 2: (H)

[1247] Prepared as described for the example above. LC/MS: t_(R)=2.94min, 560.23 (MH⁺).

EXAMPLE 228

[1248]

[1249]Benzyl-methyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1250] Prepared as described for the example above. LC/MS: t_(R)=2.08min, 478.23 (MH⁺).

EXAMPLE 229

[1251]

[1252](2-Cyclopropyl-ethyl)-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1253] Prepared as described for the example above. LC/MS: t_(R)=2.06min, 470.27 (MH⁺).

EXAMPLE 230

[1254]

[1255](2-Cyclopropyl-ethyl)-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1256] Prepared as described for the example above. LC/MS: t_(R)=2.17min, 484.28 (MH⁺).

EXAMPLE 231

[1257]

[1258]Butyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1259] Prepared as described for the example above. LC/MS: t_(R)=2.01min, 458.26 (MH⁺).

EXAMPLE 232

[1260]

[1261](2-Cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1262] Prepared as described for the example above. LC/MS: t_(R)=2.94min, 524.25 (MH⁺).

EXAMPLE 233

[1263]

[1264]Benzyl-ethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1265] Prepared as described for the example above. LC/MS: t_(R)=2.16min, 492.25 (MH⁺).

EXAMPLE 234

[1266]

[1267]Phenethyl-(2,2,2-trifluoro-ethyl)-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1268] Prepared as described for the example above. LC/MS: t_(R)=2.96min, 560.25 (MH⁺).

EXAMPLE 235

[1269]

[1270]Benzyl-butyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine, scheme 2: (H)

[1271] Prepared as described for the example above. LC/MS: t_(R)=2.56min, 520.27 (MH⁺).

EXAMPLE 236

[1272]

[1273]Benzyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1274] Prepared as described for the example above. LC/MS: t_(R)=2.40min, 506.26 (MH⁺).

EXAMPLE 237

[1275]

[1276]Ethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-amine,scheme 2: (H)

[1277] Prepared as described for the example above. LC/MS: t_(R)=1.95min, 452.28 (MH⁺).

EXAMPLE 238

[1278]

[1279]Cyclobutylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1280] Prepared as described for the example above. LC/MS: t_(R)=1.84min, 430.30 (MH⁺).

EXAMPLE 239

[1281]

[1282]Diallyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1283] Prepared as described for the example above. LC/MS: t_(R)=1.66min, 400.27 (MH⁺).

EXAMPLE 240

[1284]

[1285]Cyclopropylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1286] Prepared as described for the example above. LC/MS: t_(R)=1.68min, 416.29 (MH⁺).

EXAMPLE 241

[1287]

[1288]Bis-cyclopropylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1289] Prepared as described for the example above. LC/MS: t_(R)=1.84min, 428.29 (MH⁺).

EXAMPLE 242

[1290]

[1291]Allyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1292] Prepared as described for the example above. LC/MS: t_(R)=1.65min, 402.28 (MH⁺).

EXAMPLE 243

[1293]

[1294](2-Cyclopropyl-ethyl)-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1295] Prepared as described for the example above. LC/MS: t_(R)=1.84min, 430.31 (MH⁺).

EXAMPLE 244

[1296]

[1297]Cyclopropylmethyl-ethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1.3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine, scheme 2: (H)

[1298] Prepared as described for the example above. LC/MS: t_(R)=1.60min, 402.28 (MH⁺).

EXAMPLE 245

[1299]

[1300]Cyclobutylmethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1301] Prepared as described for the example above. LC/MS: t_(R)=1.95min, 444.33 (MH⁺)

EXAMPLE 246

[1302]

[1303]Bis-cyclopropylmethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1304] Prepared as described for the example above. LC/MS: t_(R)=1.82min, 442.31 (MH⁺).

EXAMPLE 247

[1305]

[1306]Cyclopropylmethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1307] Prepared as described for the example above. LC/MS: t_(R)=1.68min, 430.31 (MH⁺).

EXAMPLE 248

[1308]

[1309]Ethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-amine,scheme 2: (H)

[1310] Prepared as described for the example above. LC/MS: t_(R)=2.05min, 466.30 (MH⁺).

EXAMPLE 249

[1311]

[1312]Allyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1313] Prepared as described for the example above. LC/MS: t_(R)=1.78min, 416.29 (MH⁺).

EXAMPLE 250

[1314]

[1315]Cyclopropylmethyl-ethyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1316] Prepared as described for the example above. LC/MS: t_(R)=1.70min, 416.31 (MH⁺).

EXAMPLE 251

[1317]

[1318]Diallyl-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1319] Prepared as described for the example above. LC/MS: t_(R)=1.79min, 414.28 (MH⁺).

EXAMPLE 252

[1320]

[1321](2-Cyclopropyl-ethyl)-[2-ethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl-propyl-amine,scheme 2: (H)

[1322] Prepared as described for the example above. LC/MS: t_(R)=1.95min, 444.33 (MH⁺).

[1323] For Examples 253-282 LC/MS were run using the followingconditions: Column, YMC ODC S7 3.0×50 mm; run time, 3 min.

EXAMPLE 253

[1324]

[1325][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-phenethyl-propyl-amine,scheme 2: (H)

[1326] Prepared as described for the example above. LC/MS: t_(R)=1.64min, 486.27 (MH⁺).

EXAMPLE 254

[1327]

[1328][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-propyl-amine,scheme 2: (H)

[1329] Prepared as described for the example above. LC/MS: t_(R)=1.54min, 450.30 (MH⁺).

EXAMPLE 255

[1330]

[1331][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-ethyl-phenethyl-amine,scheme 2: (H)

[1332] Prepared as described for the example above. LC/MS: t_(R)=1.60min, 472.24 (MH⁺).

EXAMPLE 256

[1333]

[1334]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(3-phenyl-pyrrolidin-1-ylmethyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1335] Prepared as described for the example above. LC/MS: t_(R)=1.60min, 470.20 (MH⁺).

EXAMPLE 257

[1336]

[1337][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1.3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-propyl-amine,scheme 2: (H)

[1338] Prepared as described for the example above. LC/MS: t_(R)=1.47min, 436.26 (MH⁺).

EXAMPLE 258

[1339]

[1340]Allyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1341] Prepared as described for the example above. LC/MS: t_(R)=1.46min, Mass spec.: 422.30 (MH⁺).

EXAMPLE 259

[1342]

[1343][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(2-cyclopropyl-ethyl)-propyl-amine,scheme 2: (H)

[1344] Prepared as described for the example above. LC/MS: t_(R)=1.55min, 450.30 (MH⁺).

EXAMPLE 260

[1345]

[1346][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-dipropyl-amine,scheme 2: (H)

[1347] Prepared as described for the example above. LC/MS: t_(R)=1.45min, 424.24 (MH⁺).

EXAMPLE 261

[1348]

[1349][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-ethyl-amine,scheme 2: (H)

[1350] Prepared as described for the example above. LC/MS: t_(R)=1.51min, 436.30 (MH⁺).

EXAMPLE 262

[1351]

[1352]Dibutyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1353] Prepared as described for the example above. LC/MS: t_(R)=1.60min, 452.29 (MH⁺).

EXAMPLE 263

[1354]

[1355]Benzyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine,scheme 2: (H)

[1356] Prepared as described for the example above. LC/MS: t_(R)=1.59min, 472.32 (MH⁺).

EXAMPLE 264

[1357]

[1358]Diallyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-amine,scheme 2: (H)

[1359] Prepared as described for the example above. LC/MS: t_(R)=1.45min, 420.25 (MH⁺).

EXAMPLE 265

[1360]

[1361][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclopropylmethyl-ethyl-amine,scheme 2: (H)

[1362] Prepared as described for the example above. LC/MS: t_(R)=1.43min, 422.22 (MH⁺).

EXAMPLE 266

[1363]

[1364]Butyl-[8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-ethyl-amine,scheme 2: (H)

[1365] Prepared as described for the example above. LC/MS: t_(R)=1.48min, 424.30 (MH⁺).

EXAMPLE 267

[1366]

[1367]3-(2-Benzyl-pyrrolidin-1-ylmethyl)-8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1368] Prepared as described for the example above. LC/MS: t_(R)=1.62min, 484.26 (MH⁺).

EXAMPLE 268

[1369]

[1370][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(2-cyclopropyl-ethyl)-ethyl-amine,scheme 2: (H)

[1371] Prepared as described for the example above. LC/MS: t_(R)=1.51min, 436.32 (MH⁺).

EXAMPLE 269

[1372]

[1373][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-diethyl-amine,scheme 2: (H)

[1374] Prepared as described for the example above. LC/MS: t_(R)=1.36min, 396.25 (MH⁺).

EXAMPLE 270

[1375]

[1376][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-methyl-(2-pyridin-3-yl-ethyl)-amine,scheme 2: (H)

[1377] Prepared as described for the example above. LC/MS: t_(R)=1.31min, 459.26 (MH⁺).

EXAMPLE 271

[1378]

[1379]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(2-phenyl-pyrrolidin-1-ylmethyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1380] Prepared as described for the example above. LC/MS: t_(R)=1.57min, 470.24 (MH⁺).

EXAMPLE 272

[1381]

[1382]3-(3-Benzyl-pyrrolidin-1-ylmethyl)-8-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (M)

[1383] Prepared as described for the example above. LC/MS: t_(R)=1.64min, 484.24 (MH⁺).

EXAMPLE 273

[1384]

[1385]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(3-phenethyl-pyrrolidin-1-ylmethyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1386] Prepared as described for the example above. LC/MS: t_(R)=1.71min, 498.27 (MH⁺).

EXAMPLE 274

[1387]

[1388][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-methyl-pyridin-4-ylmethyl-amine,scheme 2: (H)

[1389] Prepared as described for the example above. LC/MS: t_(R)=1.51min, 445.22 (MH⁺).

EXAMPLE 275

[1390]

[1391]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(2-phenethyl-pyrrolidin-1-ylmethyl)-8H-113a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1392] Prepared as described for the example above. LC/MS: t_(R)=1.66min, 498.27 (MH⁺).

EXAMPLE 276

[1393]

[1394]8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-morpholin-4-ylmethyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene,scheme 2: (H)

[1395] Prepared as described for the example above. LC/MS: t_(R)=1.35min, 410.25 (MH⁺).

EXAMPLE 277

[1396]

[1397][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-methyl-pyridin-3-ylmethyl-amine,scheme 2: (H)

[1398] Prepared as described for the example above. LC/MS: t_(R)=1.34min, 445.22 (MH⁺).

EXAMPLE 278

[1399]

[1400][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-methyl-(2-pyridin-2-yl-ethyl)-amine,scheme 2: (H)

[1401] Prepared as described for the example above. LC/MS: t_(R)=1.37min, 459.20 (MH⁺).

EXAMPLE 279

[1402]

[1403][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-(1-ethyl-propyl)-amine,scheme 2: (H)

[1404] Prepared as described for the example above. LC/MS: t_(R)=1.44min, 410.30 (MH⁺).

EXAMPLE 280

[1405]

[1406][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-methyl-(2-pyridin-4-yl-ethyl)-amine,scheme 2: (H)

[1407] Prepared as described for the example above. LC/MS: t_(R)=1.30min, 459.26 (MH⁺).

EXAMPLE 281

[1408]

[1409][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-bis-(2-methoxy-ethyl)-amine,scheme 2: (H)

[1410] Prepared as described for the example above. LC/MS: t_(R)=1.46min, 456.27 (MH⁺).

EXAMPLE 282

[1411]

[1412][8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-(2-methoxy-1-methoxymethyl-ethyl)-amine,scheme 2: (H)

[1413] Prepared as described for the example above. LC/MS: t_(R)=1.44min, 442.27 (MH⁺).

[1414] The following Intermediates 95-112 may be used to synthesizeExamples 283-300.

[1415] Intermediate 95

[1416]2-Bromo-5-methyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1417] To a solution of 2-bromo-5-methyl-3H-imidazole-4-carboxylic acidethyl ester (1.00 g, 4.291 mmol) and2-bromo-N-(2,4,6-trimethyl-phenyl)-acetamide (1.209 g, 4.720 mmol) in amixture of toluene (16 mL) and acetone (8 mL) was addeddiazabicycloundecene (0.71 mL, 4.720 mmol). The resulting solution wasstirred at room temperature for 24 h. Methanol (10 mL) was added todissolve the precipitate formed, followed by the addition of silica gel(25 g). The solvent was removed under reduced pressure to dryness andthe residue was applied to a silica gel-packed column. The isolation ofthe product was achieved by column chromatography (hexanes-ethyl acetate4:1 to 1:2). Yield—0.736 g (42%). ¹H NMR (DMSO d-6, 500 MHz) δ 9.52 (s,1H), 6.86 (s, 2H), 5.15 (br s, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.38 (s,3H), 2.21 (s, 3H), 2.11 (s, 6H), 1.30 (t, J=7.1 Hz, 3H); LC/MS:t_(R)=1.46 min., MS: [M+H]=408.

[1418] Intermediate 96

[1419] 2-Methyl-6-oxo-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazol1,2-a]imidazole-3-carboxylic acid ethyl ester, scheme 5: (W)

[1420] A suspension of2-bromo-5-methyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester (17.4 mg, 0.038 mmol) and silver carbonate (11.6 mg,0.042 mmol) in sulfolane (0.5 mL) was heated at 150° C. for 4 h. Theresulting reaction mixture was cooled to room temperature and filteredthrough a short pad of celite. The final purification was achieved by areverse-phase preparative HPLC to give the desired product as whitesolid. Yield—12.2 mg (73%). ¹H NMR (DMSO d-6, 500 MHz) δ 7.04 (s, 2H),4.99 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.06(s, 6H), 1.31 (t, J=7.2 Hz, 3H); LC/MS: t_(R)=1.75 min., MS: [M+H]=328.

[1421] Intermediate 97

[1422]6-Chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1423] A solution of3-ethoxycarbonyl-2-methyl-6-oxo-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazoliumtrifluoroacetate (22.2 mg, 0.050 mmol) in phosphorus oxychloride (1 mL)was heated at 150° C. for 48 h. The excess of phosphorus oxychloride wasremoved under reduced pressure, the residue was dissolved in saturatedaqueous solution of sodium bicarbonate (20 mL) and extracted with ethylacetate (5×20 mL). The combined organic extracts were dried with MgSO₄.The solvent was removed under reduced pressure and the crude product wasdried under pump vacuum overnight. Yield—23.3 mg (99%). LC/MS:t_(R)=1.93 min., MS: [M+H]=346.

[1424] Intermediate 98

[1425]2-Bromo-5-ethyl-3-[(2,4,6-trimethylphenylcarbamoyl)methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1426] Prepared as described above for intermediate 95. MS: m/e 422(M+H)⁺.

[1427] Intermediate 99

[1428]2-Ethyl-6-oxo-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 5: (W)

[1429] Prepared as described above for intermediate 96. MS: m/e 342(M+H)⁺.

[1430] Intermediate 100

[1431]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1432] Prepared as described above for intermediate 97. MS: m/e 360(M+H)⁺.

[1433] Intermediate 101

[1434]2-Bromo-3-[(2-chloro-4,6-dimethylphenylcarbamoyl)-methyl]-5-ethyl-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1435] Prepared as described above for intermediate 95. MS: m/e 442(M+H)⁺.

[1436] Intermediate 102

[1437]7-(2-Chloro-4,6-dimethylphenyl)-2-ethyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 5: (W)

[1438] Prepared as described above for intermediate 96. MS: m/e 362(M+H)⁺.

[1439] Intermediate 103

[1440]6-Chloro-7-(2-chloro-4,6-dimethylphenyl)-2-ethyl-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1441] Prepared as described above for intermediate 97. MS: m/e 380(M+H)⁺.

[1442] Intermediate 104

[1443]2-Bromo-5-ethyl-3-[(2,4,6-trichlorophenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1444] Prepared as described above for intermediate 95. MS: m/e 482(M+H)⁺.

[1445] Intermediate 105

[1446]2-Ethyl-6-oxo-7-(2,4,6-trichlorophenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 5: (W)

[1447] Prepared as described above for intermediate 96. MS: m/e 402(M+H)⁺.

[1448] Intermediate 106

[1449]6-Chloro-2-ethyl-7-(2,4,6-trichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1450] Prepared as described above for intermediate 97. MS: m/e 420(M+H)⁺.

[1451] Intermediate 107

[1452]2-Bromo-5-ethyl-3-[(2-bromo-4-isopropylphenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1453] Prepared as described above for intermediate 95. MS: m/e 500(M+H)⁺.

[1454] Intermediate 108

[1455]2-Ethyl-6-oxo-7-(2-bromo-4-isopropylphenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 5: (W)

[1456] Prepared as described above for intermediate 96. MS: m/e 420(M+H)⁺.

[1457] Intermediate 109

[1458]6-Chloro-2-ethyl-7-(2-bromo-4-isopropylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1459] Prepared as described above for intermediate 97. MS: m/e 438(M+H)⁺.

[1460] Intermediate 110

[1461]2-Bromo-3-[(2,4-dichlorophenylcarbamoyl)-methyl]-5-ethyl-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1462] Prepared as described above for intermediate 95. MS: m/e 448(M+H)⁺.

[1463] Intermediate 111

[1464]7-(2,4-Dichlorophenyl)-2-ethyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 5: (W)

[1465] Prepared as described above for intermediate 96. MS: m/e 368(M+H)⁺.

[1466] Intermediate 112

[1467]6-Chloro-7-(2,4-dichlorophenyl)-2-ethyl-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1468] Prepared as described above for intermediate 97. MS: m/e 386(M+H)⁺.

EXAMPLE 283

[1469]

[1470]6-Chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide,

[1471] Scheme 6: (BB)

[1472] To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530mmol) in toluene (1.5 mL) at 0° C. was added 2.0M solution oftrimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solutionwas warmed to room temperature and stirred for 1 h. A solution of6-chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (32.2 mg, 0.098 mmol) in toluene (1.0 mL) was added at0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. Asolution of Rochelle's salt (2.0 mL) was added carefully at 0° C. andthe mixture was vigorously stirred for 30 min. The crude product wasextracted with ethylacetate. The combined organic extracts were driedwith MgSO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by a reverse-phase preparative HPLC. Yield—21.3 mg(42%). ¹H NMR (CD₃CN, 500 MHz) δ 7.69 (s, 1H), 7.16 (s, 2H), 3.59 (t,J=7.3 Hz, 2H), 3.39 (d, J=6.9 Hz, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.05(s, 6H), 1.68 (sextet, J=7.3 Hz, 2H), 1.11 (m, 1H), 0.90 (t, J=7.3 Hz,3H), 0.60 (m, 2H), 0.23 (m, 2H); LC/MS: t_(R)=1.71 min., MS: [M+H]=413.

EXAMPLE 284

[1473]

[1474][6-Chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-propyl-amine,scheme 6: (DD)

[1475] A solution of3-(cyclopropylmethyl-propyl-carbamoyl)-2-methyl-6-oxo-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole(31.7 mg, 0.077 mmol) in toluene (3 mL) was added a 65% solution ofRed-Al in toluene (0.12 mL, 0.384 mmol). The reaction mixture wasstirred at room temperature for 14 h. A solution of Rochelle's salt (2.0mL) was added carefully at 0° C. and the mixture was vigorously stirredfor 30 min. The crude product was extracted with ethylacetate. Thecombined organic extracts were dried with Na₂SO₄. The solvent wasremoved under reduced pressure and the crude product was purified by areverse-phase preparative HPLC. Yield—25.2 mg (64%). ¹H NMR (CD₃OD, 500MHz) δ 8.09 (s, 1H), 7.19 (s, 2H), 4.75 (s, 2H), 3.31 (t, J=6.5 Hz, 2H),3.24 (d, J=7.2 Hz, 2H), 2.44 (s, 3H), 2.39 (s, 3H), 2.06 (s, 6H), 1.24(m, 3H), 1.05 (t, J=7.4 Hz, 3H), 0.85-0.82 (m, 2H), 0.50 (m, 2H); LC/MS:t_(R)=1.43 min., MS: [M+H]=399.

EXAMPLE 285

[1476]

[1477]6-Chloro-2-ethyl-7-(2-bromo-4-isopropylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-propylamide, scheme 6: (BB)

[1478] Prepared as described for Example 283. IR(film): 1615 cm⁻¹. ¹HNMR (CDCl₃) δ 7.57 (d, J=2.0 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.29 (dd,J=8.1, 2.0 Hz, 1H), 7.22 (s, 1H), 3.60 (t, J=7.1 Hz, 2H), 3.39 (d, J=7.1Hz, 2H), 2.95 (m, 1H), 2.66 (q, J=7.6 Hz, 2H), 1.64 (m, 2H), 1.55 (s,3H), 1.40 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H), 0.54(m, 2H), 0.17 (m, 2H). MS: m/e 505(M+H)⁺.

EXAMPLE 286

[1479]

[1480]6-Chloro-2-ethyl-7-(2,4-dichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amide, scheme 6: (BB)

[1481] Prepared as described for Example 283. IR(film): 1630 cm⁻¹. ¹HNMR (CDCl₃) δ 7.60 (m, 1H), 7.42 (m, 2H), 7.27 (s, 1H), 4.41 (q, J=9.1Hz, 2H), 3.52 (d, J=6.6 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6Hz, 3H), 0.94 (m, 1H), 0.60 (m, 2H), 0.16 (m, 2H). MS: m/e 493 (M+H)⁺.

EXAMPLE 287

[1482]

[1483]6-Chloro-2-ethyl-7-(2,4-dichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N,N-dipropylamide, scheme 6: (BB)

[1484] Prepared as described for Example 283. IR(film): 1615 cm⁻¹. ¹HNMR (CDCl₃) δ 7.59 (m, 1H), 7.41 (m, 2H), 7.24 (s, 1H), 3.47 (t, J=7.1Hz, 4H), 2.65 (q, J=7.6 Hz, 2H), 1.62 (m, 4H), 1.24 (t, J=7.6 Hz, 3H),0.87 (t, J=7.1 Hz, 6H). MS: m/e 441 (M+H)⁺.

EXAMPLE 288

[1485]

[1486]3-[(N,N-Dipropylamino)methyl]-6-chloro-2-ethyl-7-(2,4-diclorophenyl)-7H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1487] Prepared as described for Example 284.

[1488]¹H NMR (DMSO-d₆) δ 7.98 (m, 1H), 7.89 (m, 1H), 7.70 (m, 2H), 4.52(s, 2H), 3.00 (q, J=7.6 Hz, 4H), 2.55 (q, J=7.6 Hz, 2H), 1.68 (m, 4H),1.12 (t, J=7.6 Hz, 3H), 0.89 (t, J=7.6 Hz, 6H). MS: m/e 427 (M+H)⁺.

EXAMPLE 289

[1489]

[1490]3-[(N-Cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amino)methyl]-6-chloro-2-ethyl-7-(2,4-diclorophenyl)-7H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1491] Prepared as described for Example 284. ¹H NMR (CDCl₃) δ 7.62 (d,J=2.0 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.47 (dd, J=8.6, 2.0 Hz, 1H),7.42 (s, 1H), 3.97 (s, 2H), 3.26 (q, J=9.6 Hz, 2H), 2.69 (q, J=7.6 Hz,2H), 2.57 (q, J=6.6 Hz, 1H), 2.47 (q, J=7.1 Hz, 1H), 1.26 (t, J=7.6 Hz,3H), 0.86 (m, 1H), 0.59 (m, 2H), 0.12 (m, 2H). MS: m/e 479 (M+H)⁺.

EXAMPLE 290

[1492]

[1493]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-propylamide, scheme 6: (BB)

[1494] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.26 (s, 1H), 6.98 (s, 2H), 3.60 (t, J=7.1 Hz, 2H), 3.39 (d, J=7.1 Hz,2H), 2.65 (q, J=7.6 Hz, 2H), 2.32 (s, 3H), 2.01 (s, 6H), 1.64 (m, 3H),1.22 (t, J=7.6 Hz, 3H), 0.88 (m, 3H), 0.54 (m, 2H), 0.16 (q, J=4.6, 6.1Hz, 2H). MS: m/e: 427 (M+H)⁺.

EXAMPLE 291

[1495]

[1496]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-butyl-N-ethylamide, scheme 6: (BB)

[1497] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.26 (s, 1H), 6.98 (s, 2H), 3.53 (m, 4H), 2.65 (q, J=7.1 Hz, 2H), 2.32(s, 3H), 2.01 (s, 6H), 1.58 (m, 4H), 1.25 (m, 6H), 0.87 (t, J=7.1 Hz,3H). MS: m/e: 415 (M+H)⁺.

EXAMPLE 292

[1498]

[1499]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N,N-dipropylamide, scheme 6: (BB)

[1500] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.29 (s, 1H), 7.02 (s, 2H), 3.50 (t, J=7.1 Hz, 4H), 2.69 (q, J=7.1, 7.6Hz, 2H), 2.36 (s, 3H), 2.05 (s, 6H), 1.64 (m, 4H), 1.26 (t, J=7.6 Hz,3H), 0.91 (overlapping d, J=7.1, 7.6 Hz, 6H). MS: m/e: 415 (M+H)⁺.

EXAMPLE 293

[1501]

[1502]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N,N-diethylamide, scheme 6: (BB)

[1503] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.28 (s, 1H), 6.98 (s, 2H), 3.56 (q, J=7.1 Hz, 4H), 2.65 (q, J=7.6 Hz,2H), 2.32 (s, 3H), 2.01 (s, 6H), 1.21 (m, 9H). MS: m/e: 387 (M+H)⁺.

EXAMPLE 294

[1504]

[1505]3-[(N-Butyl-N-ethylamino)methyl]-6-chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1506] Prepared as described for Example 284. ¹H NMR (CDCl₃, 400 MHz) δ7.99 (s, 1H), 7.11 (s, 2H), 4.54 (d, J=4.6 Hz, 2H), 3.09 (m, 4H), 2.59(q, J=7.58 Hz, 2H), 2.33 (s, 3H), 1.93 (s, 6H), 1.61 (m, 2H), 1.29 (m,6H), 1.13 (t, J=7.6 Hz, 3H), 0.89 (dd, J=7.1, 7.6 Hz, 3H). MS: m/e: 401(M+H)⁺.

EXAMPLE 295

[1507]

[1508]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N,N-diallylamide, scheme 6: (BB)

[1509] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.20 (s, 1H), 6.93 (s, 2H), 5.77 (m, 2H), 5.17 (m, 4H), 4.07 (d, J=6.1Hz, 4H), 2.62 (dd, J=7.1, 7.6 Hz, 2H), 2.27 (s, 3H), 1.96 (s, 6H), 1.17(t, J=7.6 Hz, 3H). MS: m/e: 411 (M+H)⁺.

EXAMPLE 296

[1510]

[1511]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amide, scheme 6: (BB)

[1512] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.27 (s, 1H), 6.99 (s, 2H), 4.41 (q, J=9.1 Hz, 2H), 3.53 (d, J=7.1 Hz,2H), 2.66 (q, J=7.6 Hz, 2H), 2.33 (s, 3H), 2.01 (s, 6H), 1.22 (t, J=7.6Hz, 3H), 0.93 (m, 1H), 0.59 (m, 2H), 0.15 (dd, J=4.6, 6.1 Hz, 2H). MS:m/e: 467 (M+H)⁺.

EXAMPLE 297

[1513]

[1514]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-ethyl-N-(pyridin-4-yl)methylamide, scheme 6: (BB)

[1515] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ8.58 (m, 2H), 7.32 (s, 1H), 7.22 (d, J=6.1 Hz, 2H), 6.98 (s, 2H), 4.74(s, 2H), 3.54 (dd, J=7.1, 7.6 Hz, 2H), 2.68 (dd, J=7.1, 7.6 Hz, 2H),2.32 (s, 3H), 2.01 (s, 6H). 1.21 (m, 6H). MS: m/e: 450 (M+H)⁺.

EXAMPLE 298

[1516]

[1517]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid N-cyclopropylmethyl-N-ethylamide, scheme 6: (BB)

[1518] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.27 (s, 1H), 6.97 (s, 2H), 3.69 (q, J=7.1 Hz, 2H), 3.40 (d, J=6.6 Hz,2H), 2.65 (dd, J=7.1, 7.6 Hz, 2H), 2.32 (s, 3H), 2.01 (s, 6H), 1.22 (t,J=7.1 Hz, 6H), 1.03 (m, 1H), 0.55 (m, 2H), 0.18 (dd, J=5.1, 5.6 Hz, 2H).MS: m/e: 413 (M+H)⁺.

EXAMPLE 299

[1519]

[1520]3-[(N-Cyclopropylmethyl-N-ethylamino)methyl]-6-chloro-2-ethyl-7-(2.4.6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1521] Prepared as described for Example 284. ¹H NMR (CDCl₃, 400 MHz) δ7.92 (s, 1H), 7.02 (s, 2H), 4.46 (s, 2H), 3.34 (s, 2H), 3.10 (d, J=7.1Hz, 2H), 2.74 (m, 2H), 2.34 (s, 3H), 1.97 (s, 6H), 1.41 (t, J=7.1 Hz,3H), 1.29 (t, J=7.1 Hz, 3H), 1.13 (m, 1H), 0.86 (m, 2H), 0.46 (m, 2H).MS: m/e: 399 (M+H)⁺.

EXAMPLE 300

[1522]

[1523]6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid (3,5-dimethylpiperidin-1-yl)amide, scheme 6: (BB)

[1524] Prepared as described for Example 283. ¹H NMR (CDCl₃, 400 MHz) δ7.18 (s, 1H), 6.90 (s, 2H), 4.12 (m, 2H), 2.57 (q, J=7.6 Hz, 2H), 2.36(t, J=11.6, 12.6 Hz, 2H), 2.25 (s, 3H), 1.94 (s, 6H), 1.70 (m, 4H), 1.14(t, J=7.1, 7.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 4H), 0.78 (m, 2H). MS: m/e:427 (M+H)⁺.

[1525] Intermediates 95 and 96 were used to synthesize Example 301.

EXAMPLE 301

[1526]

[1527]2-Methyl-6-oxo-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 7: (LL)

[1528] To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530mmol) in toluene (1.5 mL) at 0° C. was added 2.0M solution oftrimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solutionwas warmed to room temperature and stirred for 1 h. A solution of6-chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (20.0 mg, 0.058 mmol) in toluene (1.5 mL) was added at0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. Asolution of Rochelle's salt (2.0 mL) was added carefully at 0° C. andthe mixture was vigorously stirred for 30 min. The crude product wasextracted with ethyl acetate. The combined organic extracts were driedwith MgSO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by a reverse-phase preparative HPLC. Yield—3.6 mg(12%). ¹H NMR (CD₃CN, 500 MHz) δ 7.07 (s, 2H), 4.73 (s, 2H), 3.57 (t,J=7.1 Hz, 2H), 3.37 (d, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 2.14(s, 6H), 1.65 (sextet, J=7.3 Hz, 2H), 1.08 (m, 1H), 0.90 (t, J=7.4 Hz,3H), 0.56 (m, 2H), 0.21 (m, 2H); LC/MS: t_(R)=1.67 min., MS: [M+H]=395.

[1529] The following Intermediates 113-115 may be used to synthesizeExamples 302 and 303.

[1530] Intermediate 113

[1531]2-Bromo-5-trifluoromethyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (V)

[1532] To a solution of2-bromo-5-trifluoromethyl-3H-imidazole-4-carboxylic acid ethyl ester(3.00 g, 10.45 mmol) and 2-bromo-N-(2,4,6-trimethyl-phenyl)-acetamide(2.94 g, 11.50 mmol) in a mixture of toluene (16 mL) and acetone (8 mL)was added DBU (1.72 mL, 11.50 mmol). The resulting solution was stirredat room temperature for 5 days. Methanol (10 mL) was added to dissolvethe precipitate formed, followed by the addition of silica gel (25 g).The solvent was removed under reduced pressure to dryness and theresidue was applied to a silica gel-packed column. The isolation of theproduct was achieved by column chromatography (hexanes-ethyl acetate4:1). Yield—4.25 g (88%). LC/MS: t_(R)=1.62 min., MS: [M+H]=462.

[1533] Intermediate 114

[1534]2-Bromo-5-trifluoromethyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester, scheme 5: (W)

[1535] A suspension of2-bromo-5-trifluoromethyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylicacid ethyl ester (20.12 g, 0.044 mmol) and silver triflate (11.87 g,0.046 mol) in sulfolane (200 mL) was heated at 150° C. for 6 h. Theresulting reaction mixture was cooled to room temperature and filteredthrough a short pad of celite. The final purification was achieved by areverse-phase preparative HPLC to give the desired product as yellowishsolid. Yield—5.24 g (24%). LC/MS: t_(R)=1.89 min., MS: [M+H]=382.

[1536] Intermediate 115

[1537]6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester, scheme 6: (AA)

[1538] A solution of6-oxo-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (3.04 g, 6.137 mol) in phosphorus oxychloride (70 mL)was heated at 150° C. for 72 h. The excess of phosphorus oxychloride wasremoved under reduced pressure, the residue was dissolved in saturatedaqueous solution of sodium bicarbonate (100 mL) and extracted with ethylacetate (5×50 mL). The combined organic extracts were dried with MgSO₄.The solvent was removed under reduced pressure and the crude product wasdried under pump vacuum overnight. Yield—1.192 g (38%). LC/MS:t_(R)=2.17 min., MS: [M+H]=400.

EXAMPLE 302

[1539]

[1540]6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide, scheme 6: (BB)

[1541] To a solution of N-cyclopropylmethylpropylamine (0.22 mL, 1.530mmol) in toluene (1.5 mL) at 0° C. was added 2.0M solution oftrimethylaluminum in toluene (0.77 mL, 1.530 mmol). The clear solutionwas warmed to room temperature and stirred for 1 h. A solution of6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (37.7 mg, 0.094 mmol) in toluene (1.0 mL) was added at0° C. via cannula. The reaction mixture was heated at 80° C. for 2 h. Asolution of Rochelle's salt (2.0 mL) was added carefully at 0° C. andthe mixture was vigorously stirred for 30 min. The crude product wasextracted with ethyl acetate. The combined organic extracts were driedwith MgSO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by a reverse-phase preparative HPLC. Yield—39.5 mg(90%). LC/MS: t_(R)=1.93 min., MS: [M+H]=467.

EXAMPLE 303

[1542]

[1543][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-propyl-amine,scheme 6: (DD)

[1544] A solution of6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid cyclopropylmethyl-propyl-amide (27.2 mg, 0.058 mmol) in toluene (3mL) was added a 65% solution of Red-Al in toluene (0.10 mL, 0.320 mmol).The reaction mixture was stirred at room temperature for 14 h. Asolution of Rochelle's salt (2.0 mL) was added carefully at 0° C. andthe mixture was vigorously stirred for 30 min. The crude product wasextracted with ethyl acetate. The combined organic extracts were driedwith Na₂SO₄. The solvent was removed under reduced pressure and thecrude product was purified by a reverse-phase preparative HPLC.Yield—12.8 mg (39%). LC/MS: t_(R)=1.77 min., MS: [M+H]=453.

[1545] The following Intermediates 116 and 117 may be used to synthesizeExamples 303-347.

[1546] Intermediate 116

[1547][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-yl]-methanol,scheme 6: (CC)

[1548] To a solution of6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylicacid ethyl ester (978.3 mg, 1.904 mmol) in tetrahydrofuran (100 mL) at0° C. was added a 1.0M solution of lithium aluminum hydride intetrahydrofuran (5.71 mL, 5.71 mmol). The resulting solution was stirredat 0° C. for 10 min. Acetone (5 mL) was added and the solution was adedvia cannula to a vigorously stirred ice-cold solution of Rochelle's salt(100 mL). The product was extracted with ethyl acetate (5×50 mL) and thecombined organic extracts were dried over anhydrous Na₂SO₄. The solventwas removed in vacuo and the crude mixture was chromatographed on shortsilica gel column (hexanes-ethyl acetate 4:1) to give the desiredproduct (614.8 mg, 90%) which was pure by LC-MS. LC/MS: t_(R)=1.25 min.,MS: [M+H]=358.

[1549] Intermediate 117

[1550]2-Chloro-5-chloromethyl-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole

[1551] A solution of[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-yl]-methanol(614.8 mg, 1.718 mmol) and thionyl chloride (1.25 mL) in dichloromethanewas stirred at 0° C. for 15 min. Thionyl chloride and the solvent wereremoved in vacuo and the residue was dried under high vacuum to yieldthe desired product as a yellow solid (646.3 mg, 100%). LC/MS:t_(R)=1.46 min., MS: [MH—Cl+OMe]=373.

EXAMPLE 303

[1552]

[1553][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-propyl-amine,scheme 6: (DD)

[1554] To a solution of amine (6.1 mg, 0.054 mmol) and Hüinig's base(0.05 mL) in acetonitrile (0.5 mL) at room temperature was added slowlya solution of2-chloro-5-chloromethyl-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole(10.0 mg, 0.027 mmol) in acetonitrile (0.5 mL). The reaction mixture wasstirred overnight. The final purification was achieved by areverse-phase preparative HPLC to give the desired product as colorlessoil. Yield—9.9 mg (65%). LC/MS: t_(R)=1.77 min., MS: [M+H]=453.

EXAMPLE 304

[1555]

[1556][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1557] Prepared as described for the example above. LC/MS: t_(R)=2.31min., MS: [M+H]=494.

EXAMPLE 305

[1558]

[1559]2-Chloro-5-(3,6-dihydro-2H-pyridin-1-ylmethyl)-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1560] Prepared as described for the example above. LC/MS: t_(R)=1.59min., MS: [M+H]=423.

EXAMPLE 306

[1561]

[1562]2-Chloro-5-thiomorpholin-4-ylmethyl-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1563] Prepared as described for the example above. LC/MS: t_(R)=1.63min., MS: [M+H]=443.

EXAMPLE 307

[1564]

[1565]Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-methyl-amine,scheme 6: (DD)

[1566] Prepared as described for the example above. LC/MS: t_(R)=1.73min., MS: [M+H]=461.

EXAMPLE 308

[1567]

[1568][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-methyl-phenethyl-amine,scheme 6: (DD)

[1569] Prepared as described for the example above. LC/MS: t_(R)=1.76min., MS: [M+H]=475.

EXAMPLE 309

[1570]

[1571]Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-amine,scheme 6: (DD)

[1572] Prepared as described for the example above. LC/MS: t_(R)=1.77min., MS: [M+H]=475.

EXAMPLE 310

[1573]

[1574]Butyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-methyl-amine,scheme 6: (DD)

[1575] Prepared as described for the example above. LC/MS: t_(R)=1.62min., MS: [M+H]=427.

EXAMPLE 311

[1576]

[1577]Benzyl-butyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-aminescheme 6: (DD)

[1578] Prepared as described for the example above. LC/MS: t_(R)=1.92min., MS: [M+H]=503.

EXAMPLE 312

[1579]

[1580][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-(2-methyl-allyl)-amine,scheme 6: (DD)

[1581] Prepared as described for the example above. LC/MS: t_(R)=1.70min., MS: [M+H]=439.

EXAMPLE 313

[1582]

[1583][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-nitro-benzyl)-propyl-amine,scheme 6: (DD)

[1584] Prepared as described for the example above. LC/MS: t_(R)=2.16min., MS: [M+H]=534.

EXAMPLE 314

[1585]

[1586][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-furan-2-ylmethyl-methyl-amine,scheme 6: (DD)

[1587] Prepared as described for the example above. LC/MS: t_(R)=1.67min., MS: [M+H]=451.

EXAMPLE 315

[1588]

[1589][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,4-dichloro-benzyl)-ethyl-amine,scheme 6: (DD)

[1590] Prepared as described for the example above. LC/MS: t_(R)=2.14min., MS: [M+H]=543.

EXAMPLE 316

[1591]

[1592]5-(2-Benzyl-pyrrolidin-1-ylmethyl)-2-chloro-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1593] Prepared as described for the example above. LC/MS: t_(R)=1.80min., MS: [M+H]=501.

EXAMPLE 317

[1594]

[1595]2-Chloro-5-(3-phenyl-pyrrolidin-1-ylmethyl)-6-trifluoromethyl-1-(2,4,6-trimethyl-phenyl)-1H-imidazo[1,2-a]imidazole,scheme 6: (DD)

[1596] Prepared as described for the example above. LC/MS: t_(R)=1.78min., MS: [M+H]=487.

EXAMPLE 318

[1597]

[1598]6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amine,scheme 6: (DD)

[1599] Prepared as described for the example above. LC/MS: t_(R)=2.38min., MS: [M+H]=543.

EXAMPLE 319

[1600]

[1601][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-ethyl-amine,scheme 6: (DD)

[1602] Prepared as described for the example above. LC/MS: t_(R)=1.64min., MS: [M+H]=439.

EXAMPLE 320

[1603]

[1604][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1605] Prepared as described for the example above. LC/MS: t_(R)=2.40min., MS: [M+H]=507.

EXAMPLE 321

[1606]

[1607][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1608] Prepared as described for the example above. LC/MS: t_(R)=2.02min., MS: [M+H]=495.

EXAMPLE 322

[1609]

[1610][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1611] Prepared as described for the example above. LC/MS: t_(R)=2.29min., MS: [M+H]=481.

EXAMPLE 323

[1612]

[1613][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2,2,3,3,3-pentafluoro-propyl)-propyl-amine,scheme 6: (DD)

[1614] Prepared as described for the example above. LC/MS: t_(R)=2.38min., MS: [M+H]=531.

EXAMPLE 324

[1615]

[1616][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-phenethyl-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1617] Prepared as described for the example above. LC/MS: t_(R)=2.32min., MS: [M+H]=543.

EXAMPLE 325

[1618]

[1619][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-phenethyl-propyl-amine,scheme 6: (DD)

[1620] Prepared as described for the example above. LC/MS: t_(R)=1.85min., MS: [M+H]=503.

EXAMPLE 326

[1621]

[1622][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-phenethyl-amine,scheme 6: (DD)

[1623] Prepared as described for the example above. LC/MS: t_(R)=1.79min., MS: [M+H]=489.

EXAMPLE 327

[1624]

[1625]Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1626] Prepared as described for the example above. LC/MS: t_(R)=2.34min., MS: [M+H]=543.

EXAMPLE 328

[1627]

[1628][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-propyl-amine,scheme 6: (DD)

[1629] Prepared as described for the example above. LC/MS: t_(R)=1.76min., MS: [M+H]=467.

EXAMPLE 329

[1630]

[1631][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-ethyl-amine,scheme 6: (DD)

[1632] Prepared as described for the example above. LC/MS: t_(R)=1.71min., MS: [M+H]=453.

EXAMPLE 330

[1633]

[1634][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1635] Prepared as described for the example above. LC/MS: t_(R)=2.15min., MS: [M+H]=521.

EXAMPLE 331

[1636]

[1637][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1638] Prepared as described for the example above. LC/MS: t_(R)=2.01min., MS: [M+H]=507.

EXAMPLE 332

[1639]

[1640][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl-(4-fluoro-benzyl)-(2,2,2-trifluoro-ethyl)-amine,scheme 6: (DD)

[1641] Prepared as described for the example above. LC/MS: t_(R)=2.33min., MS: [M+H]=547.

EXAMPLE 333

[1642]

[1643]-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1644] Prepared as described for the example above. LC/MS: t_(R)=2.33min., MS: [M+H]=561.

EXAMPLE 334

[1645]

[1646][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-fluoro-benzyl)-propyl-amine,scheme 6: (DD)

[1647] Prepared as described for the example above. LC/MS: t_(R)=1.91min., MS: [M+H]=507.

EXAMPLE 335

[1648]

[1649][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-propyl-amine,scheme 6: (DD)

[1650] Prepared as described for the example above. LC/MS: t_(R)=1.75min., MS: [M+H]=467.

EXAMPLE 336

[1651]

[1652](4-Chloro-benzyl)-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1653] Prepared as described for the example above. LC/MS: t_(R)=2.42min., MS: [M+H]=577.

EXAMPLE 337

[1654]

[1655](4-Chloro-benzyl)-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine,scheme 6: (DD)

[1656] Prepared as described for the example above. LC/MS: t_(R)=2.05min., MS: [M+H]=523.

EXAMPLE 338

[1657]

[1658]Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine,scheme 6: (DD)

[1659] Prepared as described for the example above. LC/MS: t_(R)=1.86min., MS: [M+H]=489.

EXAMPLE 339

[1660]

[1661]Allyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine,scheme 6: (DD)

[1662] Prepared as described for the example above. LC/MS: t_(R)=1.67min., MS: [M+H]=539.

EXAMPLE 340

[1663]

[1664][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3-fluoro-benzyl)-propyl-amine,scheme 6: (DD)

[1665] Prepared as described for the example above. LC/MS: t_(R)=1.99min., MS: [M+H]=507.

EXAMPLE 341

[1666]

[1667][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-ethyl-amine,scheme 6: (DD)

[1668] Prepared as described for the example above. LC/MS: t_(R)=1.72min., MS: [M+H]=453.

EXAMPLE 342

[1669]

[1670][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-methoxy-ethyl)-propyl-amine,scheme 6: (DD)

[1671] Prepared as described for the example above. LC/MS: t_(R)=1.68min., MS: [M+H]=457.

EXAMPLE 343

[1672]

[1673][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine,scheme 6: (DD)

[1674] Prepared as described for the example above. LC/MS: t_(R)=2.32min., MS: [M+H]=561.

EXAMPLE 344

[1675]

[1676][6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-dipropyl-amine,scheme 6: (DD)

[1677] Prepared as described for the example above. LC/MS: t_(R)=1.68min., MS: [M+H]=441.

EXAMPLE 345

[1678]

[1679]Diallyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-amine,scheme 6: (DD)

[1680] Prepared as described for the example above. LC/MS: t_(R)=1.70min., MS: [M+H]=437.

EXAMPLE 346

[1681]

[1682]Butyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-amine,scheme 6: (DD)

[1683] Prepared as described for the example above. LC/MS: t_(R)=1.71min., MS: [M+H]=441.

EXAMPLE 347

[1684]

[1685]3-(2-Benzyl-pyrrolidin-1-ylmethyl)-2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine,scheme 7: (KK)

[1686] LC/MS: t_(R)=1.7 min., MS: [M+H]=483.

[1687] The following amine hydrochloride salts are intermediates thatwere used in many of the above examples:

[1688] Intermediate 118

[1689] 2-Cyclopropylethylamine hydrochloride

[1690] A 1M solution of borane in tetrahydrofuran (250 mL, 2 equiv.)that had been cooled to 0° C. was added to cyclopropylacetonitrile(10.00 g, 123.3 mmoles) at 0° C. under nitrogen. The stirred mixture washeated at reflux for 12 hours, cooled to 0° C., and then carefullyquenched with methanol (50 mL). The mixture was heated at reflux for 2hours and then, upon re-cooling to 0° C., treated with a solution oft-butylpyrocarbonate (37.67 g, 1.4 equiv.) in methylene chloride (25mL). The resulting mixture was stirred at room temperature overnight andthen evaporated. the residue was partitioned between ethyl acetate andwater. The organic was washed with water, brine, dried over magnesiumsulfate, and evaporated to give the crude Boc-protected amine. This wasdissolved in methylene chloride (25 mL) and treated with 4M hydrogenchloride in dioxane (77 mL, 2.5 equiv.). The mixture was stirred at roomtemperature overnight and then evaporated. The resulting white solid wastriturated with ether and the product was collected by filtration,washed with ether, and dried in vacuo (12.72 g, 85%). ¹H-NMR δ (CDCl₃)0.14 (m, 2H), 0.52 (m, 2H), 0.75 (m, 1H), 1.66 (q, 2H), 3.09 (m, 2H),8.27 (br, 3H).

[1691] Intermediate 119

[1692] 3,3,3-Trifluoroacetic acid N-hydroxysuccinimide active ester,scheme 8: (MM)

[1693] A stirred solution of 3,3,3-trifluoroacetic acid (9.7 mL, 110mmoles) and N-hydroxysuccinimide (13.92 g, 1.1 equiv.) in methylenechloride (100 mL) at 0° C. was treated with EDC hydrochloride (21.08 g,1 equiv.). The mixture was allowed to warm to room temperature. Afterstirring overnight, the solvent was evaporated and the residuepartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over magnesium sulfate, and evaporated to givethe crude active ester which was used without further purification(22.78 g, 92%). ¹H-NMR δ (CDCl₃) 2.86 (s, 4H), 3.51 (q, 2H).

[1694] Intermediate 120

[1695] Cyclopropylmethyl-3,3,3-trifluoropropyl-amine hydrochloride,scheme 8: (OO)

[1696] A stirred solution of 3,3,3-trifluoroacetic acidN-hydroxysuccinimide active ester (12.98 g, 57.65 mmoles) in methylenechloride (80 mL) at 0° C. was treated with cyclopropylmethylamine (5.0mL, 1 equiv.). The mixture was stirred at room temperature for 14 hoursand then evaporated. The residue was partitioned between ethyl acetateand water. The organic phase was washed with water, brine, dried overmagnesium sulfate, and evaporated to give the crude amide. This wasdried under high vacuum for several hours and then, under a nitrogenatmosphere at 0° C., it was carefully treated with a 1M solution ofborane in tetrahydrofuran (173 mL, 3 equiv.). The mixture was heated atreflux for 14 hours and then re-cooled to 0° C. Methanol (50 mL) wasadded very carefully to avoid excess foaming, and the mixture was heatedat reflux for 5 hours. Upon re-cooling to 0° C., a solution oft-butylpyrocarbonate (17.62 g, 1.4 equiv.) in methylene chloride (25 mL)was added. The resulting mixture was stirred at room temperatureovernight and then evaporated. the residue was partitioned between ethylacetate and water. The organic was washed with water, brine, dried overmagnesium sulfate, and evaporated to give the crude Boc-protected amine.This was dissolved in methylene chloride (25 mL) and treated with 4Mhydrogen chloride in dioxane (36 mL, 2.5 equiv.). The mixture wasstirred at room temperature overnight and then evaporated. The resultingwhite solid was triturated with ether and the product was collected byfiltration, washed with ether, and dried in vacuo (10.10 g, 86%). ¹H-NMRδ (D₂O) 0.36 (m, 2H), 0.67 (m, 2H), 1.07 (m, 1H), 2.72 (m, 2H), 2.99 (d,2H), 3.89 (t, 2H).

[1697] Similarly prepared:

[1698] Intermediate 121

[1699] 2-Cyclopropylethyl-3,3,3-trifluoropropyl-amine hydrochloride,scheme 8: (OO)

[1700]¹H-NMR δ (D₂O) 0.14 (m, 2H), 0.52 (m, 2H), 0.74 (m, 1H), 1.61 (m,2H), 2.73 (m, 2H), 3.20 (t, 2H), 3.38 (t, 2H).

[1701] Intermediate 122

[1702] n-Propyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme 8:(OO)

[1703]¹H-NMR δ (D₂O) 0.98 (t, 3H), 1.71 (q, 2H), 2.72 (m, 2H), 3.06 (t,2H), 3.36 (t, 2H).

[1704] Intermediate 123

[1705] Benzyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme 8: (OO)

[1706]¹H-NMR δ (D₂O) 2.73 (m, 2H), 3.40 (t, 2H), 4.31 (s, 2H), 7.51(brs, 5H).

[1707] Intermediate 124

[1708] p-Fluoro-benzyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme8: (OO)

[1709]¹H-NMR δ (D₂O) 2.73 (m, 2H), 3.38 (t, 2H), 4.28 (s, 2H), 7.23(ABq, 2H), 7.51 (ABq, 2H).

[1710] Intermediate 125

[1711] p-Chloro-benzyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme8: (OO)

[1712]¹H-NMR δ (D₂O) 2.72 (m, 2H), 3.39 (t, 2H), 4.29 (s, 2H), 7.49 (q,4H).

[1713] Intermediate 126

[1714] m-Fluoro-benzyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme8: (OO)

[1715]¹H-NMR δ (D₂O) 2.73 (m, 2H), 3.41 (t, 2H), 4.39 (s, 2H), 7.30 (m,3H), 7.66 (m, 1H).

[1716] Intermediate 127

[1717] 2-Phenylethyl-3,3,3-trifluoropropyl-amine hydrochloride, scheme8: (OO)

[1718]¹H-NMR δ (D₂O) 2.73 (m, 2H), 3.07 (t, 2H), 3.40 (m, 4H), 7.42 (m,5H).

[1719] Intermediate 128

[1720] Benzyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme 8: (OO)

[1721] A stirred solution of benzylamine (5.0 mL, 45.77 mmoles) andtriethylamine (6.4 mL, 1 equiv.) in methylene chloride (50 mL) at 0° C.was treated with trifluoroacetic anhydride (6.5 mL, 1 equiv.), dropwiseover 10 minutes. After 2 hours, the solvents were evaporated and theresidue partitioned between ethyl acetate and 2% phosphoric acid. Theorganic phase was washed with water and brine, dried over magnesiumsulfate, and evaporated. The crude amide was cooled to 0° C. undernitrogen and treated with ice-cold 1 M borane-tetrahydrofuran complex(137 mL, 3 equiv.). The reaction mixture was heated at reflux for 14hours and then cooled to 0° C. Methanol (50 mL) was carefully added and,when bubbling had largely ceased, the mixture was heated at reflux for 5hours. Upon cooling to room temperature, the stirred mixture was treatedwith a solution of t-butylpyrocarbonate (14.00 g, 1.4 equiv.) inmethylene chloride (25 mL). After continued stirring overnight at roomtemperature, the mixture was evaporated and the residue partitionedbetween ethyl acetate and water. The organic phase was washed with morewater and brine, dried over magnesium sulfate, and evaporated. Theresidue in methylene chloride (25 mL) was treated with 4M hydrogenchloride in dioxane (69 mL, 1.5 equiv.) and the reaction was stirred atroom temperature overnight. Evaporation gave a semi-solid that wastriturated with ether. The resulting white solid product was collectedby filtration, washed with ether, and dried in vacuo (9.28 g, 90%).¹H-NMR 8 (D₂O) 3.97 (q, 2H), 4.07 (s, 2H), 7.52 (s, 5H).

[1722] Similarly prepared:

[1723] Intermediate 129

[1724] Cyclopropylmethyl-2,2,2-trifluoroethyl-amine hydrochloride,scheme 8: (OO)

[1725]¹H-NMR δ (D₂O) 0.39 (m, 2H), 0.72 (q, 2H), 1.08 (m, 1H), 3.11 (d,2H), 4.00 (q, 2H).

[1726] Intermediate 130

[1727] Cyclobutylmethyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme8: (OO)

[1728]¹H-NMR δ (D₂O) 1.75-2.02 (m, 4H), 2.12 (m, 2H), 2.71 (m, 1H), 3.24(d, 2H), 3.93 (q, 2H).

[1729] Intermediate 131

[1730] 2-Cyclopropylethyl-2,2,2-trifluoroethyl-amine hydrochloride,scheme 8: (OO)

[1731]¹H-NMR δ (D₂O) 0.14 (m, 2H), 0.53 (m, 2H), 0.76 (m, 1H), 1.64 (q,2H), 3.30 (t, 2H), 3.98 (q, 2H).

[1732] Intermediate 132

[1733] n-Propyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme 8: (OO)

[1734]¹H-NMR δ (D₂O) 1.00 (t, 3H), 1.76 (m, 2H), 3.17 (t, 2H), 3.97 (q,2H).

[1735] Intermediate 133

[1736] p-Fluorobenzyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme8: (OO)

[1737]¹H-NMR δ (D₂O) 3.98 (q, 2H), 4.40 (s, 2H), 7.24 (t, 2H), 7.53 (m,2H).

[1738] Intermediate 134

[1739] m-Fluorobenzyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme8: (OO)

[1740]¹H-NMR δ (D₂O) 3.97 (q, 2H), 4.39 (s, 2H), 7.30 (m, 3H), 7.66 (m,1H).

[1741] Intermediate 135

[1742] p-Chlorobenzyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme8: (OO)

[1743]¹H-NMR δ (D₂O) 3.98 (q, 2H), 4.39 (s, 2H), 7.50 (m, 4H).

[1744] Intermediate 136

[1745] 2-Phenylethyl-2,2,2-trifluoroethyl-amine hydrochloride, scheme 8:(OO)

[1746]¹H-NMR δ (D₂O) 3.10 (t, 2H), 3.49 (t, 2H), 4.00 (q, 2H), 7.41 (m,5H).

[1747] Intermediate 137

[1748] Cyclopropylmethyl-2,2,3,3,3-pentafluoropropyl-aminehydrochloride, scheme 8: (OO)

[1749]¹H-NMR δ (D₂O) 0.41 (m, 2H), 0.72 (m, 2H), 1.21 (m, 1H), 3.14 (d,2H), 4.06 (t, 2H).

[1750] Intermediate 138

[1751] n-Propyl-2,2,3,3,3-pentafluoropropyl-amine hydrochloride, scheme8: (OO)

[1752]¹H-NMR δ (D₂O) 1.00 (t, 3H), 1.78 (m, 2H), 3.20 (t, 2H), 4.05 (t,2H).

[1753] Intermediate 139

[1754] bis-Cyclopropylmethyl-amine hydrochloride, scheme 8: (OO)

[1755]¹H-NMR δ (D₂O) 0.35 (m, 2H), 0.68 (m, 2H), 1.07 (m, 1H), 2.95 (d,2H).

[1756] Intermediate 140

[1757] Cyclopropylmethyl-ethyl-amine hydrochloride, scheme 8: (OO)

[1758]¹H-NMR δ (D₂O) 0.34 (m, 2H), 0.67 (m, 2H), 1.04 (m, 1H), 1.27 (t,3H), 2.90 (d, 2H), 3.08 (q, 2H).

[1759] Intermediate 141

[1760] 2-Cyclopropylethyl-ethyl-amine hydrochloride, scheme 8: (OO)

[1761]¹H-NMR δ (D₂O) 0.12 (m, 2H), 0.51 (m, 2H), 0.73 (m, 1H), 1.28 (t,3H), 1.60 (m, 2H), 3.12 (m, 4H).

[1762] Intermediate 142

[1763] 2-Cyclopropylethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1764]¹H-NMR δ (D₂O) 0.13 (m, 2H), 0.51 (m, 2H), 0.72 (m, 1H), 0.97 (t,3H), 1.58 (q, 2H), 1.66 (m, 2H), 3.00 (t, 2H), 3.13 (t, 2H).

[1765] Intermediate 143

[1766] Cyclobutylmethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1767]¹H-NMR δ (D₂O) 0.95 (t, 3H), 1.60-2.05 (m, 6H), 2.10 (m, 2H), 2.62(m, 1H), 2.96 (t, 2H), 3.06 (t, 2H).

[1768] Intermediate 144

[1769] Benzyl-propyl-amine hydrochloride, scheme 8: (OO)

[1770]¹H-NMR δ (D₂O) 0.96 (t, 3H), 1.71 (m, 2H), 3.04 (t, 2H), 4.23 (s,2H), 7.50 (m, 5H).

[1771] Intermediate 145

[1772] 3-Pyridylmethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1773]¹H-NMR δ (D₂O) 0.99 (t, 3H), 1.73 (m, 2H), 3.13 (t, 2H), 4.51 (s,2H), 8.11 (t, 1H), 8.67 (d, 1H), 8.87 (d, 1H), 8.95 (s, 1H).

[1774] Intermediate 146

[1775] 2-Pyridylmethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1776]¹H-NMR δ (D₂O) 0.97 (t, 3H), 1.71 (m, 2H), 3.14 (t, 2H), 4.50 (s,2H), 7.81 (m, 2H), 8.30 (m, 1H), 8.56 (d, 1H).

[1777] Intermediate 147

[1778] 4-Pyridylmethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1779]¹H-NMR δ (D₂O) 1.00 (t, 3H), 1.77 (m, 2H), 3.21 (t, 2H), 4.61 (s,2H), 8.18 (d, 2H), 8.91 (d, 2H).

[1780] Intermediate 148

[1781] p-Fluorobenzyl-propyl-amine hydrochloride, scheme 8: (OO)

[1782]¹H-NMR δ (D₂O) 0.96 (t, 3H), 1.73 (m, 2H), 3.03 (t, 2H), 4.22 (s,2H), 7.22 (t, 2H), 7.51 (m, 2H).

[1783] Intermediate 149

[1784] m-Fluorobenzyl-propyl-amine hydrochloride, scheme 8: (OO)

[1785]¹H-NMR δ (D₂O) 0.98 (t, 3H), 1.73 (m, 2H), 3.14 (t, 2H), 4.39 (s,2H), 7.30 (m, 3H), 7.65 (m, 1H).

[1786] Intermediate 150

[1787] p-Chlorobenzyl-propyl-amine hydrochloride, scheme 8: (OO)

[1788]¹H-NMR δ (D₂O) 0.96 (t, 3H), 1.71 (m, 2H), 3.03 (t, 2H), 4.22 (s,2H), 7.47 (q, 4H).

[1789] Intermediate 151

[1790] 2-Phenylethyl-propyl-amine hydrochloride, scheme 8: (OO)

[1791]¹H-NMR δ (D₂O) 0.95 (t, 3H), 1.69 (m, 2H), 3.05 (m, 4H), 3.32 (t,2H), 7.37 (m, 5H).

[1792] Intermediate 152

[1793] 2-Phenylethyl-ethyl-amine hydrochloride, scheme 8: (OO)

[1794]¹H-NMR δ (D₂O) 1.26 (t, 3H), 3.11 (m, 4H), 3.32 (t, 2H), 7.41 (m,5H).

[1795] Intermediate 153

[1796] Allyl-propylamine hydrochloride, scheme 8: (OO)

[1797] A stirred solution of allylamine (10.0 mL, 133.3 mmoles) inmethylene chloride (80 mL) at 0° C. was treated with propionic anhydride(8.54 mL, 0.5 equi.v), dropwise over 10 minutes. After 2 hours, thesolvents were evaporated and the residue partitioned between ethylacetate and 2% phosphoric acid. The organic phase was washed with brine,dried over magnesium sulfate, and evaporated. The crude amide in toluene(10 mL) was cooled to 0° C. under nitrogen and treated with a 3.33Msolution of Red-Al in toluene (7.1 mL, 2.5 equiv.). After stirring atroom temperature for 14 hours, the mixture was cooled to 0° C. andcarefully quenched with acetone (12 mL). The reaction was allowed towarm to room temperature and then was treated with methanol (3 mL) and,after a further 1 hour at room temperature, a solution oft-butylpyrocarbonate (2.87 g, 1.4 equiv.) in methylene chloride (5 mL).After 14 hours at room temperature, the solvents were evaporated and theresidue partitioned between ethyl acetate and 10% aqueous citric acid.The organic phase was washed with more water and brine, dried overmagnesium sulfate, and evaporated. The residue in methylene chloride (5mL) was treated with 4M hydrogen chloride in dioxane (6 mL, 2.5 equiv.)and the reaction was stirred at room temperature overnight. Evaporationgave a semi-solid that was triturated with ether. the resulting whitesolid product was collected by filtration, washed with ether, and driedin vacuo (0.760 g, 60%). ¹H-NMR 8 (D₂O) 0.97 (t, 3H), 1.70 (m, 2H), 3.01(t, 2H), 3.66 (d, 2H), 5.50 (t, 2H), 5.91 (m, 1H).

REFERENCES

[1798] 1. Kulagowski, J. J.; Moody, C. J.; Rees, C. W. Journal ofChemical Society Perkin Transaction I 1985, 2725-2733.

[1799] 2. Zhou, J.; Oh, L. M.; Bakthavatchalay, R.; PCT WO 98/42706,p16.

[1800] 3. Scherz, M. W.; Fialeix, M.; Fischer, J. B.; Reddy, N. L.;Server, A. C.; Sonders, M. S.; Tester, B. C.; Weber, E.; Wong, S.;Keana, J. F. W. Journal of Medcinal Chemistry 1990, 33, 2421-2429.

[1801] 4. Anisimova, V. A.; Kuzmenko, T. A.; Spasov, A. A.; Bocharova,I. A.; Orobinskaya, T. A. Pharmaceutical Chemistry Journal 1999, 33,361-365.

[1802] 5. Weijnen, J. G.; Koudijs, A.; Schellekens, G.; Engbersen, J.F.; Journal of Chemical Society Perkin Transaction II 1992, 829-834.

[1803] 6. Cieplik, J.; Machon, Z.; Farmaco, 1995, 50, 131-136.

[1804] 7. Basha, A.; Lipton, M.; Weinreb, S. M.; Tetrahedron Letters,1977, 4171.

[1805] 8. Bazant, V.; Capka, M.; Cerny, M.; Chvalousky, V.; Kochloefl,K.; Kraus, M.; Malek, J.; Tetrahedron Letters, 1968, 3303.

[1806] CRF₁ Receptor Binding Protocol

[1807] CRF₁ receptor antagonists, by occupying the same receptors,blocks the accessibility of the receptors to CRF, a hypothalamic factormediating body's responses to physiological and psychological stress.The following radioligand binding assay examines the ability of theantagonists to bind the CRF₁ receptors by assessing their ability tocompete with binding of CRF to the receptors in cell membrane. Compoundsof the present invention exemplified in examples 1-15 all showed K_(i)values less than 75 micromolar. See Table I.

[1808] Tissue culture and membrane preparation. IMR-32 cells were grownat 37° C. in 5% CO₂ as a monolayer in medium consisting of MEMsupplemented with 10% heat-inactivated fetal bovine serum, 0.1 mMnonessential amino acids, 1 mM sodium pyruvate and 2 mM L-glutamine.Cells were transformed by exposure to 2.5 μM 5′-bromo-2′-deoxyuridinefor 10 days. After transformation, cells were rinsed twice withphosphate-buffered saline, and incubated for 10-15 min. at 4° C. inhomogenization buffer consisting of 50 mM Tris (pH 7.2), 10 mM MgCl₂ and2 mM EGTA. Cells were transferred from plates to polypropylene tubes(16×100 mm), homogenized and centrifuged at 32,000×g for 15 min. Pelletswere resuspended by homogenization in buffer and centrifuged at 32,000×gfor 15 min. Pellets were resuspended in homogenization buffer thenstored at −80° C. until needed.

[1809] Radioligand binding assays. Membranes (150 μg/well) wereincubated with [¹²⁵I]-oCRF (100 pM) and increasing concentrations oftest compound for 100 minutes at 25° C. in a total volume of 200 μl. Theassay buffer consisted of 50 mM Tris (pH 7.2), 10 mM MgCl₂, 0.5% BSA,0.005% Triton X-100, 10 μg/mL aprotinin and 10 μg/mL leupeptin. Assayswere stopped by addition of ice-cold wash buffer (50 mM Tris, pH 7.4 and0.2% BSA). Filtration over glass fiber filters (Whatman GF/B) previouslysoaked in 50 mM Tris, pH 7.2 and 1% BSA was carried out using a Brandelcell harvester. Filters were washed with 10 mL of ice-cold wash buffer.Non-specific binding was defined with 10 μM oCRF. IC₅₀ values for oCRFand test compounds were calculated by nonlinear regression using aone-site binding curve (GraphPad Prism). TABLE I Key A < 10 nM, B < 100nM, C < 1,000 nM D < 10,000 nM Example number K_(i) (CRF-1R), nM 1 C 2 B5 B 6 B 7 B 8 B 9 B 10 B 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20C 21 D 22 D 23 D 24 D 25 D 26 D 27 B 28 B 29 C 30 B 31 B 32 B 33 B 34 C35 D 36 C 37 C 38 D 39 D 40 D 41 C 42 C 43 C 44 B 45 C 46 D 47 C 48 B 49C 50 B 54 D 55 D 56 D 57 D 58 D 59 B 60 C 61 C 62 C 63 C 64 C 65 C 66 C67 B 68 C 69 C 70 C 71 B 72 C 73 A 74 B 75 B 76 B 77 B 78 C 79 B 80 C 81C 82 B 83 B 84 C 85 D 86 C 87 C 88 C 89 C 90 C 91 C 92 C 93 B 94 C 95 B96 B 97 C 98 C 99 C 100 C 101 C 102 C 103 B 104 C 105 C 106 C 107 C 108C 109 C 110 C 111 C 112 B 113 B 114 C 115 B 116 C 117 C 118 C 119 C 120C 121 C 122 C 123 C 124 C 125 C 126 C 127 C 128 C 129 C 130 C 131 B 132C 133 C 134 C 135 B 136 C 137 C 138 B 139 D 140 C 141 C 142 D 143 D 144B 145 B 146 B 147 B 148 B 149 C 150 B 151 B 152 B 153 B 154 B 155 B 156B 157 B 158 B 159 B 160 C 161 C 162 C 163 C 164 C 165 C 166 C 167 C 168C 169 C 170 C 171 C 172 D 173 D 174 D 175 D 176 D 177 C 178 C 179 C 180D 181 D 182 D 183 D 184 D 185 D 186 D 187 B 188 B 189 C 190 C 191 C 192C 193 C 194 C 195 C 196 C 197 C 198 C 199 D 200 D 201 D 202 D 203 D 204D 205 D 206 D 207 D 208 D 209 D 210 B 211 B 212 B 213 B 214 B 215 B 216B 217 B 218 C 219 C 220 C 221 C 222 C 223 C 224 C 225 C 226 C 227 C 228C 229 C 230 C 231 C 232 C 233 D 234 D 235 D 236 D 237 A 238 A 239 B 240B 241 B 242 B 243 B 244 B 245 B 246 B 247 B 248 B 249 B 250 C 251 C 252C 253 A 254 A 255 A 256 A 257 B 258 B 259 B 260 B 261 B 262 B 263 B 264B 265 B 266 B 267 B 268 B 269 C 270 C 271 C 272 C 273 C 274 D 275 D 276D 277 D 278 D 279 D 280 D 281 D 282 D 283 B 284 B 285 C 286 A 287 A 288B 289 B 290 B 291 B 292 B 293 C 294 C 295 C 296 A 297 C 298 A 299 B 300B 301 C 302 B 303 A 304 A 305 C 306 C 307 C 308 C 309 C 310 C 311 C 312B 313 C 314 C 315 C 316 C 317 C 318 A 319 A 320 A 321 A 322 A 323 C 324C 325 B 326 A 327 B 328 B 329 B 330 A 331 A 332 C 333 B 334 B 335 A 336A 337 B 338 C 339 A 340 C 341 A 342 B 343 B 344 B 345 A 346 B 347 A

What is claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof wherein R¹ isH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl, cyano, halo,C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl orC₃₋₆alkynyl; R² is C(D)NR³R⁴, D′-D″(R³)(R⁴) or CH₂NR³R⁴ D′ is CH₂ or abond; D″ is C, C—OH or CH  wherein said C is attached to R³ by a singleor double bond; said C is attached to R⁴ by a single or double bond; provided that C is not attached to both R³ and R⁴ by double bonds; saidCH is attached to R³ and R⁴ by single bonds; said C of C—OH is attachedto R³ and R⁴ by single bonds; D is O or S; R³ and R⁴ are eachindependently selected from the group consisting of H, C₁₋₆alkyl,C₁₋₆haloalkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄alkylene-O—C₁₋₄alkyl,—C₁₋₃alkylene-C₁₋₆thioalkyl, —C₂₋₆alkylidene-(C₁₋₄alkoxy)₂,C₃₋₇cycloalkyl, —C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₆alkynyl,—C₁₋₆alkylene-CN, —C₁₋₆alkylene-heterocyclo and —C₁₋₆alkylene-aryl;wherein said aryl of said —C₁₋₆alkylene-aryl is optionally substitutedwith one to three of the same or different substituents selected fromthe group consisting of fluoro, chloro, bromo, cyano, nitro, C₁₋₄alkyland C₁₋₃alkoxy; or R³ and R⁴ together with the nitrogen to which theyare attached form a five or six-membered heterocycle, said heterocycleoptionally containing one additional heteroatom selected from the groupconsisting of N, S and O; and said heterocycle optionally substitutedwith one or more groups selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, aryl, —C₁₋₄alkylene-aryl, pyridyl and halogen; wherein saidaryl of said —C₁₋₄alkylene-aryl is optionally substituted with one tothree of the same or different substituents selected from the groupconsisting of fluoro, chloro, bromo, cyano, nitro and C₁₋₃alkoxy; X isC; Y is C; A is

 wherein X¹ is N and is attached to X; Y¹ is N and is attached to Y; Gis

 wherein Y² is CE¹ and is attached to Y¹; J is a bond; Z¹ is CE³ and isattached to Z;  wherein E¹ and E³ together form N(CH)₃,  optionallysubstituted with halogen, —CN, C₁-C₄alkyl, C₃-C₆cycloalkyl, substitutedor unsubstituted phenyl, hydroxy, C₁-C₄alkoxy, SH, C₁-C₄thioalkyl, NH₂,NH(C₁-C₄alkyl) or N(C₁-C₄alkyl)₂; Z is N—V, wherein V is phenyl,2-pyridyl or 3-pyridyl substituted with two to three of the same ordifferent substitutents selected from the group consisting of C₁₋₄alkyl,C₄alkoxy, C₁₋₆thioalkyl, C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN.2. A compound according to claim 1 wherein V is phenyl or 3-pyridyl andis substituted with two to three of the same or different substitutentsselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₆thioalkyl, C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN; saidsubstituents attached at the 2, 4 or 6-positions of said phenyl or said3-pyridyl.
 3. A compound according to claim 1 wherein V is 2-pyridyl andis substituted with two of the same or different substitutents selectedfrom the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₆thioalkyl,C₁₋₄haloalkyl, halogen, N(C₁-C₄alkyl)₂ and CN; said substituentsattached at the 3 and 5-positions of said 2-pyridyl.
 4. A compoundaccording to claim 1 wherein R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl.
 5. Acompound according to claim 1 wherein R¹ is methyl or trifluoromethyl.6. A compound according to claim 1 wherein R² is C(D)NR³R⁴ and D is 0.7. A compound according to claim 1 wherein R² is CH₂NR³R⁴.
 8. A compoundaccording to claim 1 wherein R² is D′-D″(R³)(R⁴), D is a bond and D″ isC—OH.
 9. A compound according to claim 1 wherein R² is D′-D″(R³)(R⁴), Dis a bond and D″is C or CH.
 10. A compound according to claim 1 whereinR³ and R⁴ are each independently selected from the group consisting ofH, C₁₋₆alkyl, C₁₋₆haloalkyl, —C₁₋₆hydroxyalkyl,—C₁₋₄alkylene-O—C₁₋₄alkyl, —C₁₋₃alkylene-C₁₋₆thioalkyl,—C₂₋₆alkylidene-(C₁₋₄alkoxy)₂, C₃₋₇cycloalkyl,—C₁₋₆alkylene-C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₆alkynyl and—C₁₋₆alkylene-CN.
 11. A compound according to claim 1 wherein R³ and R⁴together with the nitrogen to which they are attached form a five orsix-membered heterocycle.
 12. A compound according to claim 1 wherein Vis 2, 4, 6-trimethylphenyl.
 13. A compound according to claim 1 whereinV is 2,4-dichlorophenyl.
 14. A compound according to claim 1 wherein E¹and E³ together form N(CH)₃ optionally substituted with halogen,methoxy, methyl or nitrile.
 15. A compound according to claim 1 whereinR² is CH₂NR³R⁴, R³ is ethyl or propyl, R⁴ is —(CH₂)₂-phenyl, E¹ and E³together form N(CH)₃ optionally substituted with halogen, methoxy,methyl or nitrile.
 16. A compound according to claim 1 wherein R² isCH₂NR³R⁴, R³ is ethyl or propyl, R⁴ is —(CH₂)₂-phenyl, E¹ and E³together form N(CH)₃ optionally substituted with halogen.
 17. A compoundor pharmaceutically acceptable salt of solvate thereof selected from thegroup consisting ofEthyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-phenethyl-amine;Cyclobutylmethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-propyl-amine;[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-phenethyl-propyl-amine;[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[α]inden-3-ylmethyl]-cyclobutylmethyl-propyl-amine;[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-ethyl-phenethyl-amine;8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-3-(3-phenyl-pyrrolidin-1-ylmethyl)-8H-1,3a,7,8-tetraaza-cyclopenta[α]indene;Cyclopropylmethyl-propyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-amine;Phenethyl-[2-trifluoromethyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine;[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-phenethyl-propyl-amine;[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-ethyl-phenethyl-amine;and[8-(2-Chloro-4,6-dimethyl-phenyl)-2-methyl-8H-1,3a,7,8-tetraaza-cyclopenta[a]inden-3-ylmethyl]-(2-methoxy-1-methoxymethyl-ethyl)-amine.
 18. A methodof treating depression, anxiety, affective disorders, post-traumaticstress disorder, post-operative stress, headache, drug addiction, eatingdisorders and obesity, sudden death due to cardiac disorders, irritablebowel syndrome, hypertension, syndrome X, inflammatory disorders,stress-induced immune suppression, infertility, stress-induced insomniaand other sleep disorders, seizures, epilepsy, stroke and cerebralischemia, traumatic brain injury, yet other disorders requiringneuroprotection, drug or alcohol withdrawal symptoms, other disordersincluding tachycardia, congestive heart failure, osteoporosis, prematurebirth, psychosocial dwarfism, ulcers, diarrhea and post-operative ileuscomprising the administration of a pharmaceutical composition comprisinga compound according to claim 1.